CN115594695A

CN115594695A - Macrocyclic compound, preparation method and medical application thereof

Info

Publication number: CN115594695A
Application number: CN202210804857.3A
Authority: CN
Inventors: 张晓敏; 王珏; 张青; 贺峰; 陶维康
Original assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Current assignee: Jiangsu Hengrui Medicine Co Ltd; Shanghai Hengrui Pharmaceutical Co Ltd
Priority date: 2021-07-09
Filing date: 2022-07-08
Publication date: 2023-01-13

Abstract

The present disclosure relates to macrocyclic compounds, methods for their preparation, and their use in medicine. Specifically, the disclosure relates to a macrocyclic compound shown in a general formula (I), a preparation method thereof, a pharmaceutical composition containing the macrocyclic compound, and an application of the macrocyclic compound as a therapeutic agent, in particular an application of the macrocyclic compound as a lysine acetyltransferase (KAT) inhibitor and an application of the macrocyclic compound in preparation of drugs for treating and/or preventing cancers. The definition of each group in the general formula (I) is defined in the specification.

Description

Macrocyclic compound, preparation method and medical application thereof

Technical Field

The disclosure belongs to the field of medicines, and relates to a macrocyclic compound, a preparation method thereof and application thereof in medicines. In particular, the disclosure relates to macrocyclic compounds of formula (I), methods of their preparation, pharmaceutical compositions containing the compounds, and their use as KAT inhibitors in the treatment of cancer.

Background

Lysine acetyltransferases (KATs) are a class of enzymes that catalyze the transfer of acetyl groups from acetyl-coa to Lysine epsilon-amino groups in protein substrates. Acetylation of lysine can affect protein function, and thus plays an important regulatory role in chromosome structure, gene transcription regulation, DNA binding capacity, enzyme activity and stability, protein interactions, and intracellular localization. KATs are divided into several subfamilies, of which MYST (MOZ, YBF2/SAS3, SAS2, TIP 60) is the largest one, including KAT5 (TIP 60), KAT6A (MOZ; MYST 3), KAT6B (MORF; MYST 4), KAT7 (HBO; MYST 2) and KAT8 (MOF; MYST 1). KAT6A/B as a major member of the MYST family plays a crucial role in development, stem cell maintenance in the hematopoietic and immune systems, and tumorigenesis development and resistance.

TCGA database analysis showed that KAT6A and KAT6B amplified in multiple tumors. Wherein KAT6A is located in the 8p11-p12 amplicon region of chromosome, amplified in 10-15% of breast cancers, and has a copy number positively correlated with mRNA expression and poorly correlated with post-cure. Whereas KAT6A and KAT6B are both significantly highly expressed in breast cancer. Further subtype analysis showed that KAThere was a correlation between high expression of T6A/B and expression level of ER α, revealing that KAT6A/B may be ER ⁺ /HER2 ^- Potential targets for breast cancer.

The literature reports that the knock-down of KAT6A in the amplified luminal breast cancer cell SUM-52 of KAT6A has obvious inhibition of clone formation compared with non-tumorigenic cell MCF 10A. RNAseq analysis, however, showed that some genes were down-regulated following KAT6A knockdown, including ESR1 and hormone stress pathway related genes. Further studies showed that ER is highly expressed in KAT6A ⁺ In the breast cancer cell line T47D, CAMA, the knockdown of KAT6A could inhibit clonogenic but not in the low expressing cell lines MCF7, SKBR 3. The knockdown of KAT6A in T47D, CAMA down-regulates the expression of ER α, whereas overexpression of wild-type KAT6A in MCF7, LY2 up-regulates ER α, whereas mutants with loss of KAT activity do not, revealing the importance of KAT function. Overexpression of ER α in T47D reversed the inhibitory effect of KAT6A knockdown on clonogenic, suggesting that KAT6A function may be mediated through regulation of ER α expression. In agreement with this, an enrichment of KAT6A was found in the promoter region of the ESR1 gene. The T47D model in vivo efficacy experiment also shows the tumor inhibition effect of KAT6A knockdown and the down regulation of ER alpha. In T47D, knockdown of KAT6A and KAT6B both down-regulated ER α expression and inhibited clonogenic, and KAT6A was more potent than KAT6B, if both were knocked down at the same time, the effect was more pronounced, exhibiting additive effects. The KAT6A/B selective inhibitor CTx-648 showed antitumor activity in ER + breast cancer both in vitro and in vivo, and the expression level of KAT6A correlated somewhat with the sensitivity of CTx-648. ER highly expressed in KAT6A ⁺ In breast cancer cells, CTx-648 can down-regulate era expression, and H3K23Ac can serve as a pharmacodynamic biomarker of KAT6 inhibitors. In summary, KAT6A/B inhibitors as a single agent or with ER ⁺ /HER2 ^- Existing therapies for breast cancer, such as fulvestrant, CDK4/6 inhibitors, or even combinations of SERD, SERCA, etc., are of clinical value.

Except ER ⁺ /HER2 ^- In addition to breast cancer, KAT6A/B inhibitors have potential in brain glioma, B cell lymphoma, hepatocarcinoma, ovarian cancer, etcThe application prospect can be expanded as an indication.

Published inhibitors of KAT6 patent applications include WO2016198507A1, WO2019243491A1, WO2019043139A1, WO2019108824A1, WO2020216701A1, WO2020002587A1, WO2020254946A1, and WO2020254989A1, and the like.

Disclosure of Invention

The object of the present disclosure is to provide a compound represented by the general formula (I):

wherein:

ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

Z ¹ 、Z ² and Z ³ Are the same or different and are each independently N or CR ² ；

R ¹ And R ² The same OR different, and each is independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, halogen, hydroxy, cyano, nitro, oxo, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ³ 、-C(O)R ⁴ 、-C(O)OR ⁴ 、-OC(O)R ⁴ 、-NHC(O)OR ⁴ 、-NR ⁵ R ⁶ 、-C(O)NR ⁵ R ⁶ 、-S(O) ₂ R ⁴ and-S (O) ₂ NR ⁵ R ⁶ (ii) a Wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more R ^A Substituted;

R ^A selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, halogen, hydroxy, cyano, nitro, oxo, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^J 、-C(O)R ^f 、-C(O)OR ^f 、-OC(O)R ^f 、-NHC(O)OR ^f 、-NR ^g R ^h 、-C(O)NR ^g R ^h 、-S(O) ₂ R ^f and-S (O) ₂ NR ^g R ^h (ii) a Wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of alkyl, alkoxy, hydroxyalkyl, haloalkyl, heterocyclylalkyl, heteroarylalkyl, haloalkoxy, alkenyl, alkynyl, halogen, hydroxy, cyano, nitro, oxo, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ^J1 、-C(O)R ^f1 、-C(O)OR ^f1 、-OC(O)R ^f1 、-NHC(O)OR ^f1 、-NR ^g1 R ^h1 、-C(O)NR ^g1 R ^h1 、-S(O) ₂ R ^f1 and-S (O) ₂ NR ^g1 R ^h1 Is substituted with one or more substituents of (1);

l is- (CR) ^a R ^b ) _m -, any one of them- (CR) ^a R ^b ) -optionally substituted by one-N (R) ^k ) -, -O-or-S (O) r-;

L ₁ and L ₂ Are the same or different and are each independently absent or- (CR) ^c R ^d ) _n -；

W ₁ And W ₂ Are the same or different and are each independently selected from the group consisting of-O-, -S-and-NR ^e -；

R ^a 、R ^b 、R ^c And R ^d The same or different, and each is independently selected from the group consisting of hydrogen atom, hydroxyl group, alkyl group, alkoxy group, haloalkyl group, hydroxyalkyl group, alkenyl group, alkynyl group, haloalkoxy group, halogen, cyano group, amino group, nitro group, cycloalkyl group, heterocyclic group, aryl group, and heteroaryl group;

or, one or more R ^a And R ^b Together with the same carbon atom to which they are attached form a 3-to 8-membered cycloalkyl group or a 3-to 8-membered heterocyclyl group, wherein the 3-to 8-membered heterocyclyl group contains one or more of N, O or S (O) _r And said 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkyl, alkoxy, haloalkyl, heterocyclylalkyl heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, hydroxyalkyl, alkenyl, alkynyl, haloalkoxy, halogen, cyano, amino,Nitro, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or, any two R ^a Together with the different carbon atoms to which they are each attached form a 3-to 8-membered cycloalkyl group or a 3-to 8-membered heterocyclyl group, wherein one or more of N, O or S (O) are contained within the 3-to 8-membered heterocyclyl group _r And said 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkyl, alkoxy, haloalkyl, heterocyclylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, hydroxyalkyl, alkenyl, alkynyl, haloalkoxy, halogen, cyano, amino, nitro, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^e and R ^k Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkenyl groups, alkynyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups;

R ³ 、R ^J and R ^J1 Are the same or different and are each independently selected from the group consisting of cycloalkyl, heterocyclyl, aryl, and heteroaryl; wherein said cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkyl, alkoxy, haloalkyl, heterocyclylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, hydroxyalkyl, alkenyl, alkynyl, haloalkoxy, halogen, cyano, amino, nitro, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁴ 、R ^f and R ^f1 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein said alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally selected from the group consisting of hydroxy, alkyl, alkoxy, haloalkyl, heterocyclylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, hydroxyalkyl, alkenyl, alkynyl, haloalkoxy, halogen, cyano, amino, nitroOxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ⁵ 、R ⁶ 、R ^g 、R ^h 、R ^g1 and R ^h1 Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group; wherein said alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkyl, alkoxy, haloalkyl, heterocyclylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, hydroxyalkyl, alkenyl, alkynyl, haloalkoxy, halogen, cyano, amino, nitro, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or, R ⁵ And R ⁶ Together with the N atom to which they are attached form a 3-to 8-membered heterocyclic group, or R ^g And R ^h Together with the linking N atom form a 3-to 8-membered heterocyclic group, or R ^g1 And R ^h1 Together with the N atom to which they are attached form a 3-to 8-membered heterocyclic group containing one or more of N, O or S (O) _r Said heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkyl, alkoxy, haloalkyl, heterocyclylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, hydroxyalkyl, alkenyl, alkynyl, haloalkoxy, halogen, cyano, amino, nitro, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

m is selected from 1,2,3, 4, 5,6,7,8, 9 and 10;

n is selected from 1,2 and 3;

r is selected from 0,1 and 2; and is

p is selected from 1,2,3 and 4.

In some embodiments of the disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein L ₁ And L ₂ Is absent.

In some embodiments of the disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein W ₁ And W ₂ Are all-O-.

In some embodiments of the present disclosure, the compound represented by formula (I) or a pharmaceutically acceptable salt thereof is a compound represented by formula (II) or a pharmaceutically acceptable salt thereof:

wherein:

R ^2a and R ^2c Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy and 3 to 8 membered cycloalkyl;

R ^2b is- (CR) ^u R ^v ) _s -5 to 10 membered heteroaryl, wherein said 5 to 10 membered heteroaryl is optionally selected from halogen, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl, C _1-6 Haloalkyl and C _1-6 Substituted with one or more substituents of haloalkoxy; r ^u And R ^v Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl radical, C _1-6 Haloalkyl and C _1-6 A haloalkoxy group;

s is selected from 0,1 and 2;

ring A, L, R ¹ And p is as defined in formula (I).

In some embodiments of the disclosure, a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R ^2a Is a hydrogen atom, R ^2c Selected from hydrogen atom, halogen, hydroxy, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl radical, C _1-6 Haloalkyl, C _1-6 Haloalkoxy and 3 to 8 membered cycloalkyl; preferably, R ^2a Is a hydrogen atom, R ^2c Selected from hydrogen, halogen, hydroxy, C _1-6 Alkyl and C _1-6 An alkoxy group; more preferably still, the first and second liquid crystal compositions are,R ^2a and R ^2c Are all hydrogen atoms.

In some embodiments of the present disclosure, a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein:

R ^2b is- (CH) ₂ ) _0-3 -5 to 6 membered heteroaryl, wherein said 5 to 6 membered heteroaryl is optionally selected from halogen, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl radical, C _1-6 Haloalkyl and C _1-6 Substituted with one or more substituents of haloalkoxy;

preferably, R ^2b is-CH ₂ -5 to 6 membered heteroaryl, wherein said 5 to 6 membered heteroaryl is optionally selected from halogen, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl radical, C _1-6 Haloalkyl and C _1-6 Substituted with one or more substituents of haloalkoxy;

more preferably, R ^2b is-CH ₂ -5 to 6 membered heteroaryl, wherein said 5 to 6 membered heteroaryl is optionally selected from halogen, hydroxy, C _1-6 Alkyl and C _1-6 Substituted with one or more substituents in the hydroxyalkyl group;

most preferably, R ^2b is-CH ₂ -5-membered heteroaryl.

In some embodiments of the disclosure, a compound of formula (II) or a pharmaceutically acceptable salt thereof, wherein R ^2b Is composed of

G is N or C; r ^3a Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl radical, C _1-6 Haloalkyl and C _1-6 A haloalkoxy group; preferably, R ^3a Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 Alkyl and C _1-6 A hydroxyalkyl group; more preferably, R ^3a Is a hydrogen atom; t is selected from 1,2 and 3.

R ^3a Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl, C _1-6 Haloalkyl and C _1-6 Haloalkoxy, preferably selected from hydrogen, halogen, hydroxy, C _1-6 Alkyl and C _1-6 Hydroxyalkyl groups, more preferably hydrogen atoms; and t is 1 or 2; preferably, R ^2b Is composed of

In some embodiments of the present disclosure, a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein ring a is 6-to 10-membered aryl or 5-to 10-membered heteroaryl, said 6-to 10-membered aryl preferably being phenyl or naphthyl; the 5-to 10-membered heteroaryl group is preferably a pyridyl group, a quinolyl group and a benzoxazolyl group.

In some embodiments of the present disclosure, the compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof, wherein ring a is a 6 to 10 membered aryl, preferably phenyl.

In some embodiments of the disclosure, a compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, wherein

Is composed of

Wherein R is ¹ And p is as defined in formula (I).

In some embodiments of the present disclosure, the compound of formula (I) or formula (II), or a pharmaceutically acceptable salt thereof, is a compound of formula (III):

wherein:

R ^3a are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl, C _1-6 Haloalkyl and C _1-6 A haloalkoxy group;

t is 1 or 2;

L、R ¹ and p is as defined in formula (I).

In some embodiments of the disclosure, a compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein R is ^a And R ^b Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; preferably, R ^a And R ^b Are all hydrogen atoms.

In some embodiments of the disclosure, a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein L is- (CH) ₂ ) _m -, any one of them-CH ₂ -optionally substituted by one-N (R) ^k ) -, -O-or-S (O) r-; r is ^k R, m are as defined in formula (I).

In some embodiments of the disclosure, a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein L is- (CH) ₂ ) _m -, any one of them-CH ₂ -optionally substituted by-O-; m is as defined in formula (I).

In some embodiments of the disclosure, a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein L is- (CH) ₂ ) _m -, any one of them-CH ₂ -optionally substituted by-O-; and m is selected from 1,2,3, 4, 5 and 6.

In some embodiments of the disclosure, a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein L is- (CH) ₂ ) _m1 -Y-(CH ₂ ) _m2 -; y is selected from-CH ₂ -, -O-and-S-; m1 is selected from 1,2,3 and 4; m2 is selected from 1,2,3, 4 and 5.

In some embodiments of the disclosure, a compound of formula (I), (II) or (III), or a pharmaceutically acceptable salt thereof, wherein L is- (CH) ₂ ) _m -, and m is selected from 1,2,3, 4, 5 and 6.

In some embodiments of the present disclosure, the compound of formula (I), formula (II) or formula (III), or a pharmaceutically acceptable salt thereof, wherein L is selected from- (CH) ₂ ) ₂ -、-(CH ₂ ) ₃ -、-(CH ₂ ) ₄ -、-(CH ₂ ) ₅ -and- (CH) ₂ ) ₂ O(CH ₂ ) ₂ -。

In some embodiments of the present disclosure, the compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, is a compound of formula (IV), or a pharmaceutically acceptable salt thereof:

wherein:

m is selected from 1,2,3, 4, 5 and 6;

R ¹ 、R ^3a and t is as defined in formula (III).

In some embodiments of the present disclosure, a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, wherein R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, cyano, C _1-6 Alkyl radical, C _1-6 Hydroxyalkyl radical, C _1-6 Haloalkyl, C _1-6 Alkoxy radical, C _1-6 Haloalkoxy, 3-to 8-membered cycloalkyl, 3-to 8-membered cycloalkyloxy, C _1-6 Alkoxy radical C _1-6 Alkyl, -C (O) OCH ₃ and-C (O) NHCH ₃ (ii) a Preferably, R ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkoxy radical C _1-6 Alkyl radical, C _1-6 Hydroxyalkyl and C _1-6 A haloalkyl group; further preferably, R ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkoxy group; more preferably, R ¹ Is C _1-6 An alkoxy group; most preferably, R ¹ Is methoxy.

In some embodiments of the disclosure, a compound of formula (I), formula (II), formula (III), or formula (IV), or a pharmaceutically acceptable salt thereof, wherein R ¹ Are the same or different and are each independently selected from a hydrogen atom, a fluorine atom and a methoxy group.

In some embodiments of the present disclosure, the compound of formula (I), (II) or (III) or a pharmaceutically acceptable salt thereof, wherein p is 1 or2, preferably 1.

In some embodiments of the disclosure, a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^c And R ^d Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group; preferably, R ^c And R ^d Are all hydrogen atoms.

In some embodiments of the present disclosure, a compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein n is 1 or2, preferably 1.

In some embodiments of the disclosure, the compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R ^e Selected from hydrogen atoms, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group.

In some embodiments of the disclosure, the compound of formula (I), formula (II), or formula (III), or a pharmaceutically acceptable salt thereof, wherein R is ^k Selected from hydrogen atoms, C _1-6 Alkyl radical, C _1-6 Haloalkyl and C _1-6 A hydroxyalkyl group.

In some embodiments of the present disclosure, the compound of formula (I), (II), (III) or (IV), or a pharmaceutically acceptable salt thereof, wherein R is ³ Selected from 3 to 8 membered cycloalkyl, 3 to 12 membered heterocyclyl, 6 to 10 membered aryl and 5 to 10 membered heteroaryl; wherein said 3 to 8 membered ringAlkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl are each independently optionally selected from halogen, amino, cyano, nitro, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl radical, C _1-6 Alkoxy, oxo, and 3 to 8-membered cycloalkyl.

In some embodiments of the disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R is ⁴ Is selected from C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl; wherein said C _1-6 Alkyl, 3-to 8-membered cycloalkyl, 3-to 12-membered heterocyclyl, 6-to 10-membered aryl and 5-to 10-membered heteroaryl are each independently optionally selected from halogen, amino, cyano, nitro, hydroxy, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl, C _1-6 Alkoxy, oxo, and 3 to 8-membered cycloalkyl.

In some embodiments of the disclosure, the compound of formula (I), formula (II), formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R is ⁵ And R ⁶ Are the same or different and are each independently selected from the group consisting of a hydrogen atom, C _1-6 Alkyl radical, C _1-6 Haloalkyl, C _1-6 Hydroxyalkyl and 3 to 8 membered cycloalkyl.

In some embodiments of the disclosure, the compound of formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein R is ^3a Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 Alkyl and C _1-6 A hydroxyalkyl group; more preferably, R ^3a Is a hydrogen atom.

In some embodiments of the disclosure, the compound of formula (III) or formula (IV) or a pharmaceutically acceptable salt thereof, wherein t is 1.

In some embodiments of the disclosure, a compound of formula (III) or a pharmaceutically acceptable salt thereof, wherein L is- (CH) ₂ ) _m1 -Y-(CH ₂ ) _m2 -; y is selected from-CH ₂ -, -O-and-S-; m1 is selected from 1,2,3 and 4; m2 is selected from 1,2,3, 4 and 5; r ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Alkoxy radical C _1-6 Alkyl radical, C _1-6 Hydroxyalkyl and C _1-6 A haloalkyl group; p is 1 or 2; r is ^3a Is a hydrogen atom; and t is 1.

In some embodiments of the present disclosure, a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein m is selected from 1,2,3, 4, 5, and 6; r ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkoxy group; r ^3a Is a hydrogen atom; and t is 1.

In some embodiments of the present disclosure, a compound of formula (IV) or a pharmaceutically acceptable salt thereof, wherein m is selected from 1,2,3, 4, 5, and 6; r is ¹ Selected from the group consisting of a hydrogen atom, a fluorine atom and a methoxy group; r ^3a Is a hydrogen atom; and t is 1.

Table a typical compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a compound represented by general formula (IA):

wherein:

m is an amino protecting group, preferably allyl;

ring A, L ₁ 、L ₂ 、L、W ₁ 、W ₂ 、Z ¹ 、Z ² 、Z ³ 、R ¹ And p is as defined in formula (I).

Another aspect of the disclosure relates to a compound represented by formula (IIA) or a salt thereof:

wherein:

m is an amino protecting group, preferably allyl;

ring A, L, R ¹ 、R ^2a 、R ^2b 、R ^2c And p is as defined in formula (II).

Another aspect of the disclosure relates to a compound represented by general formula (IIIA):

wherein:

m is an amino protecting group, preferably allyl;

R ¹ 、R ^3a l, p and t are as defined in formula (III).

Another aspect of the present disclosure relates to a compound represented by the general formula (IVA):

wherein:

m is an amino protecting group, preferably allyl;

R ¹ 、R ^3a m and t are as defined in formula (IV).

Table B typical intermediate compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a compound represented by the general formula (IB'):

wherein:

x is a leaving group, preferably halogen, more preferably bromine;

ring A, M, L ₁ 、L ₂ 、L、W ₁ 、W ₂ 、Z ¹ 、Z ² 、Z ³ 、R ¹ And p is as defined in formula (IA).

Another aspect of the present disclosure relates to a compound represented by general formula (IIB'):

wherein:

x is a leaving group, preferably halogen, more preferably bromine;

ring A, M, L, R ¹ 、R ^2a 、R ^2b 、R ^2c And p is as defined in formula (IIA).

Another aspect of the disclosure relates to a compound represented by formula (IIIB'):

wherein:

x is a leaving group, preferably halogen, more preferably bromine;

M、R ¹ 、R ^3a l, p and t are as defined in formula (IIIA).

Another aspect of the present disclosure relates to a compound represented by formula (IVB'):

wherein:

x is a leaving group, preferably halogen, more preferably bromine;

M、R ¹ 、R ^3a m and t are as defined in formula (IVA).

Table C typical intermediate compounds of the present disclosure include, but are not limited to:

another aspect of the present disclosure relates to a method of preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof, comprising:

removing amino protecting group from the compound shown in the general formula (IA) or the salt thereof to obtain the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof,

wherein:

m is an amino protecting group, preferably allyl;

ring A, L ₁ 、L ₂ 、L、W ₁ 、W ₂ 、Z ¹ 、Z ² 、Z ³ 、R ¹ And p is as defined in formula (I)。

Another aspect of the present disclosure relates to a method of preparing a compound represented by the general formula (II) or a pharmaceutically acceptable salt thereof, the method comprising:

removing amino protecting group from the compound shown in the general formula (IIA) or salt thereof to obtain a compound shown in the general formula (II) or pharmaceutically acceptable salt thereof,

wherein:

m is an amino protecting group, preferably allyl;

ring A, L, R ¹ 、R ^2a 、R ^2b 、R ^2c And p is as defined in formula (II).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (III), or a pharmaceutically acceptable salt thereof, comprising:

removing the amino protecting group from the compound shown in the general formula (IIIA) or the salt thereof to obtain the compound shown in the general formula (III) or the pharmaceutically acceptable salt thereof,

wherein:

m is an amino protecting group, preferably allyl;

R ¹ 、R ^3a l, p and t are as defined in formula (III).

Another aspect of the present disclosure relates to a method of preparing a compound of formula (IV) or a pharmaceutically acceptable salt thereof, comprising:

removing amino protecting group from the compound represented by the general formula (IVA) or a salt thereof to obtain a compound represented by the general formula (IV) or a pharmaceutically acceptable salt thereof,

wherein:

m is an amino protecting group, preferably allyl;

R ¹ 、R ^3a m and t are as defined in formula (IV).

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (IA) or a salt thereof, the method comprising:

subjecting the compound represented by the general formula (IB') or a salt thereof to intramolecular nucleophilic substitution reaction to obtain a compound represented by the general formula (IA) or a salt thereof,

wherein:

x is a leaving group, preferably halogen, more preferably bromine;

Another aspect of the present disclosure relates to a process for preparing a compound of formula (IIA) or a salt thereof, comprising:

a compound represented by the general formula (IIB') or a salt thereof, undergoes an intramolecular nucleophilic substitution reaction to give a compound represented by the general formula (IIA) or a salt thereof,

wherein:

x is a leaving group, preferably halogen, more preferably bromine;

Another aspect of the present disclosure relates to a method of preparing a compound represented by formula (IIIA) or a salt thereof, the method comprising:

subjecting the compound represented by the general formula (IIIB') or a salt thereof to intramolecular nucleophilic substitution reaction to obtain a compound represented by the general formula (IIIA) or a salt thereof,

wherein:

x is a leaving group, preferably halogen, more preferably bromine;

M、R ¹ 、R ^3a l, p and t are as defined in formula (IIIA).

Another aspect of the present disclosure relates to a method of preparing a compound represented by general formula (IVA) or a salt thereof, the method comprising:

a compound represented by the general formula (IVB') or a salt thereof, which undergoes an intramolecular nucleophilic substitution reaction to give a compound represented by the general formula (IVA) or a salt thereof,

wherein:

x is a leaving group, preferably halogen, more preferably bromine;

M、R ¹ 、R ^3a m and t are as defined in formula (IVA).

Another aspect of the present disclosure relates to a pharmaceutical composition comprising a compound of the present disclosure represented by formula (I), formula (II), formula (III), formula (IV), or table a, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable carriers, diluents, or excipients.

The disclosure further relates to the use of a compound of formula (I), formula (II), formula (III), formula (IV) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, in the preparation of a medicament for inhibiting KAT; wherein said KAT is preferably KAT6, more preferably KAT6A and/or KAT6B.

The disclosure further relates to compounds of formula (I), formula (II), formula (III), formula (IV) or shown in Table A, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions comprising the sameUse for the preparation of a medicament for the treatment and/or prevention of cancer; wherein the cancer is selected from lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, brain cancer, melanoma, anal cancer, liver cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, hodgkin's disease, esophageal cancer, colorectal cancer (e.g., colon cancer, rectal cancer), small intestine cancer, stomach cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, penile cancer, testicular cancer, prostate cancer, leukemia, B-cell lymphoma, bladder cancer, urinary tract cancer, ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal cord tumor, glioma, brain glioma, pituitary adenoma, and squamous cell carcinoma; preferably breast cancer, prostate cancer, lung cancer (such as non-small cell lung cancer, small cell lung cancer), pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, glioma, B-cell lymphoma, liver cancer and leukemia; wherein the breast cancer is preferably ER ⁺ Breast cancer or ER ⁺ /HER2 ^- Breast cancer; wherein the lung cancer (such as non-small cell lung cancer, small cell lung cancer) is preferably non-small cell lung cancer; wherein the prostate cancer is preferably castration-resistant prostate cancer.

The present disclosure further relates to a method of inhibiting KAT, wherein the KAT is preferably KAT6, more preferably KAT6A and/or KAT6B, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), formula (II), formula (III), formula (IV) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure also relates to a method of treating and/or preventing KAT mediated diseases, wherein said KAT is preferably KAT6, more preferably KAT6A and/or KAT6B, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula (I), (II), (III), (IV) or shown in table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same.

The present disclosure further relates to a method of treating and/or preventing cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), formula (II),A compound of formula (III), formula (IV) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same; wherein the cancer is selected from lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, brain cancer, melanoma, anal cancer, liver cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulval cancer, hodgkin's disease, esophageal cancer, colorectal cancer (e.g., colon cancer, rectal cancer), small intestine cancer, stomach cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, penile cancer, testicular cancer, prostate cancer, leukemia, B-cell lymphoma, bladder cancer, urinary tract cancer, ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal cord tumor, glioma, brain glioma, pituitary adenoma, and squamous cell carcinoma; preferably breast cancer, prostate cancer, lung cancer (such as non-small cell lung cancer, small cell lung cancer), pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, brain glioma, B-cell lymphoma, liver cancer and leukemia; wherein the breast cancer is preferably ER ⁺ Breast cancer or ER ⁺ /HER2 ^- Breast cancer; wherein the lung cancer (such as non-small cell lung cancer, small cell lung cancer) is preferably non-small cell lung cancer; wherein the prostate cancer is preferably castration-resistant prostate cancer.

The present disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IV) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament.

The present disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IV) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for inhibiting KAT, wherein KAT is preferably KAT6, more preferably KAT6A and/or KAT6B.

The present disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IV) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a KAT inhibitor, wherein the KAT is preferably KAT6, more preferably KAT6A and/or KAT6B.

The present disclosure also relates to a compound of formula (I), formula (II), formula (III), formula (IV) or table a or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use in the treatment and/or prevention of a KAT mediated disease, wherein the KAT is preferably KAT6, more preferably KAT6A and/or KAT6B.

The present disclosure further relates to a compound of formula (I), formula (II), formula (III), formula (IV) or table a, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising the same, for use as a medicament for the treatment and/or prevention of cancer; wherein the cancer is selected from lung cancer (e.g., non-small cell lung cancer, small cell lung cancer), mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, brain cancer, melanoma, anal cancer, liver cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulval cancer, hodgkin's disease, esophageal cancer, colorectal cancer (e.g., colon cancer, rectal cancer), small intestine cancer, stomach cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, penile cancer, testicular cancer, prostate cancer, leukemia, B-cell lymphoma, bladder cancer, urinary tract cancer, ureter cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal cord tumor, glioma, brain glioma, pituitary adenoma, and squamous cell carcinoma; preferably breast cancer, prostate cancer, lung cancer (such as non-small cell lung cancer, small cell lung cancer), pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, glioma, B-cell lymphoma, liver cancer and leukemia; wherein the breast cancer is preferably ER ⁺ Breast cancer or ER ⁺ /HER2 ^- Breast cancer; wherein the lung cancer (such as non-small cell lung cancer, small cell lung cancer) is preferably non-small cell lung cancer; wherein the prostate cancer is preferably castration-resistant prostate cancer.

In some embodiments of the disclosure, the KAT6 is KAT6A and/or KAT6B.

In some embodiments of the present disclosure, the cancer is breast cancer.

In some embodiments of the disclosure, the breast cancer is ER ⁺ Breast cancer.

In some embodiments of the disclosure, the breast cancer is ER ⁺ /HER2 ^- Breast cancer.

In some embodiments of the disclosure, the breast cancer is locally advanced or metastatic ER ⁺ /HER2 ^- Breast cancer.

In some embodiments of the disclosure, the lung cancer (e.g., non-small cell lung cancer, small cell lung cancer) is non-small cell lung cancer.

In some embodiments of the disclosure, the lung cancer (e.g., non-small cell lung cancer, small cell lung cancer) is locally advanced or metastatic non-small cell lung cancer.

In some embodiments of the present disclosure, the prostate cancer is castration-resistant prostate cancer.

In some embodiments of the disclosure, the prostate cancer is locally advanced or metastatic castration resistant prostate cancer.

For convenience, certain well-known abbreviations may be used herein, including: estrogen receptor positivity (ER) ⁺ ) Human epidermal growth factor receptor 2 negative (HER 2) ^- ) Non-small cell lung cancer (NSCLC) and castration-resistant prostate cancer (CRPC).

The active compounds may be formulated in a form suitable for administration by any suitable route, using one or more pharmaceutically acceptable carriers, to formulate the compositions of the disclosure by conventional means. Thus, the active compounds of the present disclosure may be formulated in a variety of dosage forms for oral administration, injection (e.g., intravenous, intramuscular, or subcutaneous), inhalation, or insufflation. The compounds of the present disclosure may also be formulated in dosage forms such as tablets, hard or soft capsules, aqueous or oily suspensions, emulsions, injections, dispersible powders or granules, suppositories, lozenges, or syrups.

As a general guide, the active compound is preferably administered in a unit dose or in a manner such that the patient can self-administer it in a single dose. The unit dose of a compound or composition of the present disclosure may be expressed in the form of a tablet, capsule, cachet, bottled liquid, powder, granule, lozenge, suppository, reconstituted powder, or liquid. A suitable unit dose may be from 0.1 to 1000mg.

The pharmaceutical compositions of the present disclosure may contain, in addition to the active compound, one or more excipients selected from the following: fillers (diluents), binders, wetting agents, disintegrants, excipients, and the like. Depending on the method of administration, the compositions may contain from 0.1 to 99% by weight of active compound.

Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be inert excipients, granulating agents, disintegrating agents, binding agents and lubricating agents. These tablets may be uncoated or they may be coated by known techniques which mask the taste of the drug or delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.

Oral formulations may also be provided in soft gelatin capsules wherein the active ingredient is mixed with an inert solid diluent or wherein the active ingredient is mixed with a water soluble carrier or an oil vehicle.

Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending, dispersing or wetting agents. Aqueous suspensions may also contain one or more preservatives, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, or in a mineral oil. The oil suspension may contain a thickener. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable preparation. These compositions can be preserved by the addition of an antioxidant.

The pharmaceutical compositions of the present disclosure may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, or a mineral oil or a mixture thereof. Suitable emulsifiers may be naturally occurring phospholipids, and the emulsions may also contain sweetening, flavoring, preservative and antioxidant agents. Such formulations may also contain a demulcent, a preservative, a colorant and an antioxidant.

The pharmaceutical compositions of the present disclosure may be in the form of a sterile injectable aqueous solution. Among the acceptable vehicles or solvents that may be employed are water, ringer's solution and isotonic sodium chloride solution. The sterile injectable preparation may be a sterile injectable oil-in-water microemulsion in which the active ingredient is dissolved in an oil phase, and the injection or microemulsion may be injected into the bloodstream of a patient by local mass injection. Alternatively, it may be desirable to administer the solution and microemulsion in a manner that maintains a constant circulating concentration of the disclosed compounds. To maintain such a constant concentration, a continuous intravenous delivery device may be used. An example of such a device is an intravenous pump of the model Deltec CADD-PLUS. TM. 5400.

The pharmaceutical compositions of the present disclosure may be in the form of sterile injectable aqueous or oleaginous suspensions for intramuscular and subcutaneous administration. The suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable, non-toxic diluent or solvent. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. Any blend fixed oil may be used for this purpose. In addition, fatty acids can also be prepared into injections.

The compounds of the present disclosure may be administered in the form of suppositories for rectal administration. These pharmaceutical compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid in the rectum and therefore will melt in the rectum to release the drug.

Dispersible powders and granules of the compounds of the present disclosure can be administered by the addition of water to prepare an aqueous suspension. These pharmaceutical compositions may be prepared by mixing the active ingredient with dispersing or wetting agents, suspending agents, or one or more preservatives.

As is well known to those skilled in the art, the dosage of a drug administered depends on a variety of factors, including, but not limited to: the activity of the particular compound used, the age of the patient, the weight of the patient, the health of the patient, the behavior of the patient, the diet of the patient, the time of administration, the mode of administration, the rate of excretion, the combination of drugs, the severity of the disease, and the like; in addition, the optimal treatment regimen, such as mode of treatment, daily amount of compound or type of pharmaceutically acceptable salt, can be verified according to conventional treatment protocols.

Description of the terms

Unless stated to the contrary, terms used in the specification and claims have the following meanings.

The term "alkyl" refers to a saturated aliphatic hydrocarbon group which is a straight or branched chain group containing 1 to 20 carbon atoms (i.e., C) _1-20 Alkyl), preferably alkyl (i.e., C) containing 1 to 12 (e.g., 1,2,3, 4, 5,6,7,8, 9,10, 11, and 12) carbon atoms _1-12 Alkyl), more preferably an alkyl group having 1 to 6 carbon atoms (i.e., C) _1-6 Alkyl). Non-limiting examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, n-heptyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl 2,3-dimethylpentyl group, 2,4-dimethylpentyl group, 2,2-dimethylpentyl group, 3,3-dimethylpentyl group, 2-ethylpentyl group, 3-ethylpentyl group, n-octyl group, 2,3-dimethylhexyl group, 2,4-dimethylhexyl group, 2,5-dimethylhexyl group, 2,2-dimethylhexyl group, 3,3-dimethylhexyl group, 4,4-dimethylhexyl group, 2-ethylhexyl group, 3-ethylhexyl group, 4-ethylhexyl group, 2-methyl-2-ethylpentyl group, 2-methyl-3-ethylpentyl group, n-nonyl group, 2-methyl-2-ethylhexyl group, 2-methyl-3-ethylhexyl group, 2,2-diethylpentyl group, n-decyl group, 3,3-diethylhexyl group, 2,2-diethylhexyl group, and various branched chain isomers thereof, and the like. Alkyl groups may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkenyl" refers to a radical in the moleculeAlkyl compounds containing at least one carbon-carbon double bond, wherein alkyl is as defined above, having 2 to 12 (e.g. 2,3, 4, 5,6,7,8, 9,10, 11 or 12) carbon atoms (i.e. C) _2-12 Alkenyl). The alkenyl group is preferably an alkenyl group having 2 to 6 carbon atoms (i.e., C) _2-6 Alkenyl). The alkenyl group may be substituted or unsubstituted, and when substituted, the substituent is preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkynyl" refers to an alkyl compound containing at least one carbon-carbon triple bond in the molecule, wherein alkyl is as defined above and has 2 to 12 (e.g., 2,3, 4, 5,6,7,8, 9,10, 11, or 12) carbon atoms (i.e., C) _2-12 Alkynyl). The alkynyl group is preferably an alkynyl group having 2 to 6 carbon atoms (i.e., C) _2-6 Alkynyl). Alkynyl groups may be substituted or unsubstituted, and when substituted, the substituents are preferably selected from one or more of alkoxy, halogen, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "cycloalkyl" refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, the cycloalkyl ring containing from 3 to 20 (e.g., 3, 4, 5,6,7,8, 9,10, 11,12, 13, 14,15, 16,17, 18, 19, or 20) carbon atoms (i.e., 3 to 20 membered cycloalkyl groups), preferably 3 to 12 carbon atoms (i.e., 3 to 12 membered cycloalkyl groups), preferably 3 to 8 (e.g., 3, 4, 5,6,7, and 8) carbon atoms (i.e., 3 to 8 membered cycloalkyl groups), more preferably 3 to 6 carbon atoms (i.e., 3 to 6 membered cycloalkyl groups). Non-limiting examples of monocyclic cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like; polycyclic cycloalkyl groups include spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl groups.

The term "spirocycloalkyl" refers to a5 to 20 membered (e.g., 5,6,7,8, 9,10, 11,12, 13, 14,15, 16,17, 18, 19, or 20 ring atoms) (i.e., a5 to 20 membered spirocycloalkyl) polycyclic group having a single ring sharing a single carbon atom (referred to as a spiro atom), which may contain one or more double bonds. Preferably 6 to 14 membered (i.e. 6 to 14 membered spirocycloalkyl), more preferably 7 to 10 membered (e.g. 7,8,9 or 10 membered) (i.e. 7 to 10 membered spirocycloalkyl). Spirocycloalkyl groups are classified into a single spirocycloalkyl group, a double spirocycloalkyl group and a multi spirocycloalkyl group, preferably a single spirocycloalkyl group and a double spirocycloalkyl group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered spirocycloalkyl. Non-limiting examples of spirocycloalkyl groups include:

the term "fused cyclic alkyl" refers to a5 to 20 membered (e.g., 5,6,7,8, 9,10, 11,12, 13, 14,15, 16,17, 18, 19, or 20 ring atoms) (i.e., a5 to 20 membered fused cyclic alkyl), each ring in the system sharing an all carbon polycyclic group of an adjacent pair of carbon atoms with the other rings in the system, wherein one or more of the rings may contain one or more double bonds. Preferably 6 to 14 (i.e. 6 to 14 fused ring alkyl) members, more preferably 7 to 10 (e.g. 7,8,9 or 10) members (i.e. 7 to 10 fused ring alkyl). Polycyclic fused cycloalkyl groups such as bicyclic, tricyclic, tetracyclic, etc. may be classified according to the number of constituent rings, and bicyclic and tricyclic groups are preferred, and 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered, and 6-membered/6-membered bicyclic fused cycloalkyl groups are more preferred. Non-limiting examples of fused ring alkyl groups include:

the term "bridged cycloalkyl" refers to a5 to 20 membered (e.g., 5,6,7,8, 9,10, 11,12, 13, 14,15, 16,17, 18, 19, or 20 carbon atoms) (i.e., a5 to 20 membered bridged cycloalkyl), any two rings sharing two all-carbon polycyclic groups of carbon atoms not directly attached, which may contain one or more double bonds. Preferably 6 to 14 membered (i.e. 6 to 14 membered bridged cycloalkyl), more preferably 7 to 10 membered (e.g. 7,8,9 or 10 membered) (i.e. 7 to 10 membered bridged cycloalkyl). They may be classified into bicyclic, tricyclic, tetracyclic, etc. polycyclic bridged cycloalkyl groups according to the number of constituent rings, and preferably bicyclic, tricyclic and tetracyclic, more preferably bicyclic and tricyclic. Non-limiting examples of bridged cycloalkyl groups include:

the cycloalkyl ring includes a cycloalkyl ring (including monocyclic cycloalkyl, spirocycloalkyl, fused ring alkyl, and bridged cycloalkyl) fused to an aryl, heteroaryl, or heterocycloalkyl ring as described above, wherein the rings attached together with the parent structure are cycloalkyl, non-limiting examples of which include

Etc.; preferably, it is

Cycloalkyl groups may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "alkoxy" refers to-O- (alkyl), wherein alkyl is as defined above. Non-limiting examples of alkoxy groups include: methoxy, ethoxy, propoxy and butoxy. Alkoxy groups may be optionally substituted or unsubstituted, and when substituted, are preferably one or more groups independently selected from the group consisting of D atoms, halogen, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heterocyclyl" refers to a saturated or partially unsaturated mono-or polycyclic cyclic substituent comprising from 3 to 20 ring atoms (e.g., 3, 4, 5,6,7,8, 9,10, 11,12, 13, 14,15, 16,17, 18, 19, or 20 ring atoms) (i.e., a 3-to 20-membered heterocyclyl group) wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen, and sulfur, which may optionally be oxo (i.e., form a sulfoxide or sulfone), but does not include a ring moiety of-O-, -O-S-, or-S-, with the remaining ring atoms being carbon. Preferably 3 to 12 (e.g. 3, 4, 5,6,7,8, 9,10, 11 and 12) ring atoms (i.e. 3 to 12 membered heterocyclyl groups) of which 1 to 4 (e.g. 1,2,3 and 4) are heteroatoms; more preferably 3 to 8 ring atoms (e.g., 3, 4, 5,6,7 and 8) (i.e., 3 to 8 membered heterocyclyl), wherein 1-3 (e.g., 1,2 and 3) are heteroatoms; more preferably 3 to 6 ring atoms (i.e. 3 to 6 membered heterocyclyl), of which 1-3 are heteroatoms; most preferably 5 or 6 ring atoms (i.e. 5 to 6 membered heterocyclyl) are included, of which 1-3 are heteroatoms. Non-limiting examples of monocyclic heterocyclyl groups include pyrrolidinyl, tetrahydropyranyl, 1,2,3,6-tetrahydropyridinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, and the like. Polycyclic heterocyclic groups include spiro heterocyclic groups, fused heterocyclic groups, and bridged heterocyclic groups.

The term "spiroheterocyclyl" refers to 5 to 20 membered (e.g., 5,6,7,8, 9,10, 11,12, 13, 14,15, 16,17, 18, 19 or 20 ring atoms) (i.e., a5 to 20 membered spiroheterocyclyl) polycyclic heterocyclic group having one atom (referred to as a spiro atom) in common between monocyclic rings, wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), with the remaining ring atoms being carbon. It may contain one or more double bonds. Preferably 6 to 14 membered (i.e. 6 to 14 membered spiroheterocyclyl), more preferably 7 to 10 membered (e.g. 7,8,9 or 10 membered) (i.e. 7 to 10 membered spiroheterocyclyl). Spiro heterocyclic groups are classified into a single spiro heterocyclic group, a double spiro heterocyclic group and a multi spiro heterocyclic group, preferably a single spiro heterocyclic group and a double spiro heterocyclic group, according to the number of spiro atoms shared between rings. More preferably 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/5-membered or 5-membered/6-membered mono spiroheterocyclyl. Non-limiting examples of spiro heterocyclic groups include:

the term "fused heterocyclyl" refers to 5 to 20 membered (e.g. 5,6,7,8, 9,10, 11,12, 13, 14,15, 16,17, 18, 19 or 20 ring atoms) (i.e. 5 to 20 membered fused heterocyclyl) polycyclic heterocyclic groups in which each ring in the system shares an adjacent pair of atoms with the other rings in the system, one or more of the rings may contain one or more double bonds in which one or more of the ring atoms is a heteroatom selected from nitrogen, oxygen and sulphur, which may optionally be oxo (i.e. to form a sulfoxide or sulfone), the remaining ring atoms being carbon. Preferably 6 to 14 membered (i.e. 6 to 14 membered fused heterocyclyl), more preferably 7 to 10 membered (e.g. 7,8,9 or 10 membered) (i.e. 7 to 10 membered fused heterocyclyl). They are classified into bicyclic, tricyclic, tetracyclic and other polycyclic fused heterocyclic groups according to the number of constituting rings, preferably bicyclic and tricyclic, more preferably 3-membered/4-membered, 3-membered/5-membered, 3-membered/6-membered, 4-membered/4-membered, 4-membered/5-membered, 4-membered/6-membered, 5-membered/4-membered, 5-membered/5-membered, 5-membered/6-membered, 6-membered/3-membered, 6-membered/4-membered, 6-membered/5-membered and 6-membered/6-membered bicyclic fused heterocyclic groups. Non-limiting examples of fused heterocyclic groups include:

the term "bridged heterocyclyl" refers to a5 to 14 membered (e.g., 5,6,7,8, 9,10, 11,12, 13 or 14 ring atoms) (i.e., a5 to 14 membered bridged heterocyclyl) polycyclic heterocyclic group in which any two rings share two atoms not directly connected, which may contain one or more double bonds, wherein one or more ring atoms is a heteroatom selected from nitrogen, oxygen and sulfur, which may optionally be oxo (i.e., to form a sulfoxide or sulfone), and the remaining ring atoms are carbon. Preferably 6 to 14 membered (i.e. 6 to 14 membered bridged heterocyclyl), more preferably 7 to 10 membered (e.g. 7,8,9 or 10 membered) (i.e. 7 to 10 membered bridged heterocyclyl). They may be classified into polycyclic bridged heterocyclic groups such as bicyclic, tricyclic, and tetracyclic rings according to the number of constituent rings, and preferably bicyclic, tricyclic, and tetracyclic rings, and more preferably bicyclic and tricyclic rings. Non-limiting examples of bridged heterocyclic groups include:

the heterocyclyl ring includes heterocyclyl groups (including monocyclic heterocyclyl, spiro heterocyclyl, fused heterocyclyl and bridged heterocyclyl groups) as described above fused to an aryl, heteroaryl or cycloalkyl ring wherein the ring to which the parent structure is attached is heterocyclyl, non-limiting examples of which include:

and the like.

The heterocyclyl group may be substituted or unsubstituted and when substituted may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "aryl" refers to a 6 to 14 membered (e.g., 6,7,8,9, 10,11, 12, 13, or 14 ring atoms) all carbon monocyclic or fused polycyclic (fused polycyclic being a ring sharing adjacent pairs of carbon atoms) group (i.e., 6 to 14 membered aryl), preferably 6 to 10 membered (i.e., 6 to 10 membered aryl), such as phenyl and naphthyl, having a conjugated pi-electron system. Such aryl rings include those wherein the aryl ring as described above is fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring attached to the parent structure is an aryl ring, non-limiting examples of which include:

aryl groups may be substituted or unsubstituted and, when substituted, may be substituted at any available point of attachment, the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The term "heteroaryl" refers to a heteroaromatic system (i.e., 5-to 14-membered heteroaryl) containing 1 to 4 (e.g., 1,2,3, and 4) heteroatoms, 5 to 14 (e.g., 5,6,7,8, 9,10, 11,12, 13, or 14) ring atoms, wherein the heteroatoms are selected from oxygen, sulfur, and nitrogen. Heteroaryl is preferably 5 to 10 membered (e.g., 5,6,7,8, 9 or 10 membered) (i.e., 5 to 10 membered heteroaryl), more preferably 5 or 6 membered (i.e., 5 to 6 membered heteroaryl), and most preferably 5 membered (i.e., 5 membered heteroaryl), such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, pyridazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, and the like. The heteroaryl ring includes a heteroaryl fused to an aryl, heterocyclyl, or cycloalkyl ring as described above, wherein the ring that is attached to the parent structure is a heteroaryl ring, non-limiting examples of which include:

heteroaryl groups may be substituted or unsubstituted, and when substituted, may be substituted at any available point of attachment, with the substituents preferably being selected from one or more of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyloxy, heterocyclyloxy, hydroxy, hydroxyalkyl, cyano, amino, nitro, cycloalkyl, heterocyclyl, aryl and heteroaryl.

The above-mentioned cycloalkyl, heterocyclyl, aryl and heteroaryl groups include residues derived from the parent ring atom by removal of one hydrogen atom, or residues derived from the parent ring atom by removal of two hydrogen atoms from the same or two different ring atoms, i.e., "cycloalkylene", "heterocyclylene", "arylene" and "heteroarylene".

The term "amino protecting group" refers to a group which is easily removed and introduced into an amino group so that the amino group remains unchanged when the reaction is carried out at other sites of the molecule. Non-limiting examples include: (trimethylsilyl) ethoxymethyl, tetrahydropyranyl, t-butyloxycarbonyl (Boc), acetyl, benzyl, allyl, and p-methoxybenzyl, and the like. These groups may be optionally substituted with 1 to 3 substituents selected from halogen, alkoxy and nitro.

A "leaving group", or leaving group, an atom or functional group that is removed from a larger molecule in a chemical reaction, is a term used in nucleophilic substitution and elimination reactions. In nucleophilic substitution reactions, the reactant attacked by the nucleophile is called the substrate (substrate), and the atom or group of atoms cleaved from the substrate molecule with a pair of electrons is called the leaving group. Groups that accept electrons easily and have a strong ability to bear negative charges are good leaving groups. The lower the pKa of the conjugate acid of the leaving group, the easier it is for the leaving group to be cleaved from other molecules. The reason is that the tendency to exist as an anion (or an electrically neutral leaving group) is enhanced when the pKa of its conjugate acid is smaller and the corresponding leaving group does not need to be bound to another atom. Common leaving groups include, but are not limited to, halogen, -OTs, or-OH.

The term "heterocyclylalkyl" refers to an alkyl group substituted with one or more heterocyclyl groups, wherein heterocyclyl and alkyl are as defined above.

The term "heteroarylalkyl" refers to an alkyl group substituted with one or more heteroaryl groups, wherein heteroaryl and alkyl are as defined above.

The term "cycloalkyloxy" refers to cycloalkyl-O-wherein cycloalkyl is as defined above.

The term "heterocyclyloxy" refers to heterocyclyl-O-, wherein heterocyclyl is as defined above.

The term "haloalkyl" refers to an alkyl group substituted with one or more halogens, wherein alkyl is as defined above.

The term "haloalkoxy" refers to an alkoxy group substituted with one or more halogens, wherein the alkoxy group is as defined above.

The term "hydroxyalkyl" refers to an alkyl group substituted with one or more hydroxyl groups, wherein alkyl is as defined above.

The term "halogen" refers to fluorine, chlorine, bromine or iodine.

The term "hydroxy" refers to-OH.

The term "amino" refers to the group-NH ₂ 。

The term "cyano" refers to — CN.

The term "nitro" means-NO ₂ 。

The term "oxo" or "oxo" means "= O".

The term "carbonyl" refers to C = O.

The term "carboxy" refers to-C (O) OH.

"Allyl" refers to Allyl.

"Bn" refers to benzyl.

"MOM" refers to methoxymethyl.

The disclosed compounds may exist in specific stereoisomeric forms. The term "stereoisomers" refers to isomers that are identical in structure but differ in the arrangement of the atoms in space. It includes cis and trans (or Z and E) isomers, (-) -and (+) -isomers, (R) -and (S) -enantiomers, diastereomers, (D) -and (L) -isomers, tautomers, atropisomers, conformers, and mixtures thereof (e.g., racemates, mixtures of diastereomers). Additional asymmetric atoms may be present in substituents in the compounds of the present disclosure. All such stereoisomers, as well as mixtures thereof, are included within the scope of the present disclosure. Optically active (-) -and (+) -isomers, (R) -and (S) -enantiomers, and (D) -and (L) -isomers can be prepared by chiral synthesis, chiral reagents, or other conventional techniques. One isomer of a compound of the present disclosure may be prepared by asymmetric synthesis or chiral auxiliary, or, when a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl) is contained in the molecule, a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then diastereoisomeric resolution is performed by a conventional method known in the art to obtain pure isomers. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography.

In the chemical structure of the compounds described in this disclosure, a bond

Indicates that there is noAssigned configuration, i.e. if chiral isomers are present in the chemical structure, the bond

Can be that

Or

Or at the same time contain

And

two configurations.

The compounds of the present disclosure may exist in different tautomeric forms, and all such forms are included within the scope of the present disclosure. The term "tautomer" or "tautomeric form" refers to a structural isomer that exists in equilibrium and is readily converted from one isomeric form to another. It includes all possible tautomers, i.e. in the form of a single isomer or in the form of a mixture of said tautomers in any ratio. Non-limiting examples include: keto-enol, imine-enamine, lactam-lactim, and the like. Examples of lactam-lactam equilibria are shown below:

when referring to pyrazolyl, it is understood to include any one of the following two structures or a mixture of two tautomers:

all tautomeric forms are within the scope of the disclosure, and the naming of the compounds does not exclude any tautomers.

The compounds of the present disclosure include all suitable isotopic derivatives of the compounds thereof. The term "isotopic derivative" refers to a compound wherein at least one atom is replaced by an atom having the same atomic number but a different atomic mass. Examples of isotopes that can be incorporated into compounds of the present disclosure include stable and radioactive isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, bromine, and iodine, and the like, for example, respectively ² H (deuterium, D), ³ H (tritium, T), ¹¹ C、 ¹³ C、 ¹⁴ C、 ¹⁵ N、 ¹⁷ O、 ¹⁸ O、 ³² p、 ³³ p、 ³³ S、 ³⁴ S、 ³⁵ S、 ³⁶ S、 ¹⁸ F、 ³⁶ Cl、 ⁸² Br、 ¹²³ I、 ¹²⁴ I、 ¹²⁵ I、 ¹²⁹ I and ¹³¹ i and the like, preferably deuterium.

Compared with the non-deuterated drugs, the deuterated drugs have the advantages of reducing toxic and side effects, increasing the stability of the drugs, enhancing the curative effect, prolonging the biological half-life of the drugs and the like. All isotopic variations of the compounds of the present disclosure, whether radioactive or not, are intended to be encompassed within the scope of the present disclosure. Each available hydrogen atom attached to a carbon atom may be independently replaced by a deuterium atom, where replacement by deuterium may be partial or complete, partial replacement by deuterium meaning replacement of at least one hydrogen by at least one deuterium.

When a position is specifically designated as deuterium (D), that position is understood to be deuterium having an abundance that is at least 1000 times greater than the natural abundance of deuterium (which is 0.015%) (i.e., at least 15% of deuterium incorporation). The compound of examples may have a natural abundance of deuterium greater than deuterium of at least 1000 times an abundance of deuterium (i.e., at least 15% deuterium incorporation), at least 2000 times an abundance of deuterium (i.e., at least 30% deuterium incorporation), at least 3000 times an abundance of deuterium (i.e., at least 45% deuterium incorporation), at least 3340 times an abundance of deuterium (i.e., at least 50.1% deuterium incorporation), at least 3500 times an abundance of deuterium (i.e., at least 52.5% deuterium incorporation), at least 4000 times an abundance of deuterium (i.e., at least 60% deuterium incorporation), at least 4500 times an abundance of deuterium (i.e., at least 67.5% deuterium incorporation), at least 5000 times an abundance of deuterium (i.e., at least 75% deuterium incorporation), at least 5500 times an abundance of deuterium (i.e., at least 82.5% deuterium incorporation), at least 6000 times an abundance of deuterium (i.e., at least 90% deuterium incorporation), at least 6333.3 times an abundance of deuterium (i.e., at least 95% deuterium incorporation), at least 6466.7 times an abundance of deuterium (i.97% of deuterium), at least 99% abundance of deuterium (i.99.99.99.99% deuterium incorporation of deuterium, or at least 6633.3.99% of deuterium incorporation of deuterium.

"optional" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where the event or circumstance occurs or does not. For example, "a heterocyclic group optionally (optionally) substituted with an alkyl group" means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group.

"substituted" means that one or more hydrogen atoms, preferably 1 to 5, more preferably 1 to 3, of the hydrogen atoms in the group are independently substituted with a corresponding number of substituents. Those skilled in the art are able to ascertain (by experiment or theory) without undue effort, substitutions that are possible or impossible. For example, amino or hydroxyl groups having free hydrogen may be unstable in combination with carbon atoms having unsaturated (e.g., olefinic) bonds.

"pharmaceutical composition" means a mixture containing one or more compounds described herein or pharmaceutically acceptable salts or prodrugs thereof, in admixture with other chemical components, as well as other components such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to facilitate administration to an organism, facilitate absorption of the active ingredient and exert biological activity.

"pharmaceutically acceptable salts" refers to salts of the disclosed compounds which are safe and effective for use in a mammalian body and which possess the requisite biological activity. Salts may be prepared separately during the final isolation and purification of the compound, or by reacting the appropriate group with an appropriate base or acid. Bases commonly used to form pharmaceutically acceptable salts include inorganic bases such as sodium hydroxide and potassium hydroxide, and organic bases such as ammonia. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids as well as organic acids.

The term "therapeutically effective amount" with respect to a drug or pharmacologically active agent refers to an amount of drug or agent sufficient to achieve, or at least partially achieve, the desired effect. The determination of a therapeutically effective amount varies from person to person, depending on the age and general condition of the recipient and also on the particular active substance, and an appropriate therapeutically effective amount in an individual case can be determined by a person skilled in the art according to routine tests.

The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit/risk ratio, and effective for the intended use.

As used herein, the singular forms "a," "an," and "the" include plural references and vice versa unless the context clearly dictates otherwise.

When the term "about" is applied to a parameter such as pH, concentration, temperature, etc., it is meant that the parameter may vary by ± 10%, and sometimes more preferably within ± 5%. As will be appreciated by those skilled in the art, when the parameters are not critical, the numbers are generally given for illustrative purposes only and are not limiting.

Synthesis of the Compounds of the disclosure

In order to achieve the purpose of the present disclosure, the present disclosure adopts the following technical solutions:

scheme one

The preparation method of the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof comprises the following steps:

(d) The compound shown in the general formula (IA) or the salt thereof is subjected to amino protecting group removal under the action of tetrakis (triphenylphosphine) palladium and 1,3-dimethyl barbituric acid to obtain the compound shown in the general formula (I) or the pharmaceutically acceptable salt thereof,

wherein:

m is an amino protecting group, preferably allyl;

Scheme two

The preparation method of the compound shown in the general formula (II) or the pharmaceutically acceptable salt thereof comprises the following steps:

(d) Removing amino protecting group of the compound shown in the general formula (IIA) or salt thereof under the action of tetrakis (triphenylphosphine) palladium and 1,3-dimethyl barbituric acid to obtain the compound shown in the general formula (II) or pharmaceutically acceptable salt thereof,

wherein:

m is an amino protecting group, preferably allyl;

ring A, L, R ¹ 、R ^2a 、R ^2b 、R ^2c And p is as defined in formula (II).

Scheme three

The preparation method of the compound shown in the general formula (III) or the pharmaceutically acceptable salt thereof comprises the following steps:

(a) Subjecting a compound represented by the general formula (IIIB) or a salt thereof to intramolecular nucleophilic substitution reaction under the action of a base and optionally under the action of a catalyst (preferably sodium iodide or potassium iodide) to obtain a compound represented by the general formula (IIIC) or a salt thereof;

(b) Carrying out reduction reaction on the compound shown in the general formula (IIIC) or salt thereof under the action of a reducing agent to obtain a compound shown in a general formula (IIID) or salt thereof;

(c) Reacting a compound shown as a general formula (IIID) or a salt thereof with methane sulfonyl chloride under the action of alkali to obtain a compound shown as an intermediate general formula (IIIE) or a salt thereof;

subjecting the intermediate compound shown in the general formula (IIIE) or salt thereof and the compound shown in the general formula (IIIF) or salt thereof to nucleophilic substitution reaction under the action of alkali to obtain the compound shown in the general formula (IIIA) or salt thereof;

(d) Removing amino protecting groups of the compound shown in the general formula (IIIA) or a salt thereof under the action of tetrakis (triphenylphosphine) palladium and 1,3-dimethyl barbituric acid to obtain a compound shown in the general formula (III) or a pharmaceutically acceptable salt thereof;

wherein:

R ⁿ is C _1-6 Alkyl, preferably methyl;

m is an amino protecting group, preferably allyl;

x is a leaving group, preferably halogen, more preferably bromine;

R ¹ 、R ^3a l, p and t are as defined in formula (III).

Scheme four

The preparation method of the compound shown in the general formula (IV) or the pharmaceutically acceptable salt thereof comprises the following steps:

(a) A compound represented by the general formula (IVB) or a salt thereof, which undergoes an intramolecular nucleophilic substitution reaction under the action of a base and optionally under the action of a catalyst (preferably sodium iodide or potassium iodide) to give a compound represented by the general formula (IVC) or a salt thereof;

(b) Carrying out reduction reaction on the compound shown in the general formula (IVC) or salt thereof under the action of a reducing agent to obtain a compound shown in the general formula (IVD) or salt thereof;

(c) Reacting a compound shown as a general formula (IVD) or a salt thereof with methanesulfonyl chloride under the action of alkali to obtain a compound shown as an intermediate general formula (IVE) or a salt thereof;

subjecting the intermediate compound shown in the general formula (IVE) or salt thereof and the compound shown in the general formula (IIIF) or salt thereof to nucleophilic substitution reaction under the action of alkali to obtain the compound shown in the general formula (IVA) or salt thereof;

(d) Removing amino protecting groups of the compound shown in the general formula (IVA) or a salt thereof under the action of tetrakis (triphenylphosphine) palladium and 1,3-dimethyl barbituric acid to obtain a compound shown in the general formula (IV) or a pharmaceutically acceptable salt thereof;

wherein:

R ⁿ is C _1-6 Alkyl, preferably methyl;

m is an amino protecting group, preferably allyl;

x is a leaving group, preferably halogen, more preferably bromine;

R ¹ 、R ^3a m and t are as defined in formula (IV).

Scheme five

wherein:

m is an amino protecting group, preferably allyl;

R ¹ 、R ^3a l, p and t are as defined in formula (III).

Scheme six

wherein:

m is an amino protecting group, preferably allyl;

R ¹ 、R ^3a m and t are as defined in formula (IV).

Scheme seven

The preparation method of the compound shown in the general formula (IA) or the salt thereof comprises the following steps:

(c ') the compound represented by the general formula (IB') or a salt thereof undergoes an intramolecular nucleophilic substitution reaction under the action of a base and optionally under the action of a catalyst (preferably sodium iodide or potassium iodide) to give a compound represented by the general formula (IA) or a salt thereof,

wherein:

x is a leaving group, preferably halogen, more preferably bromine;

Scheme eight

The preparation method of the compound shown in the general formula (IIA) or the salt thereof comprises the following steps:

(c ') subjecting the compound represented by the general formula (IIB') or a salt thereof to intramolecular nucleophilic substitution reaction under the action of a base and optionally under the action of a catalyst (preferably sodium iodide or potassium iodide) to obtain a compound represented by the general formula (IIA) or a salt thereof,

wherein:

x is a leaving group, preferably halogen, more preferably bromine;

Scheme nine

The preparation method of the compound shown in the general formula (IIIA) or the salt thereof comprises the following steps:

(c ') the compound represented by the general formula (IIIB') or a salt thereof is subjected to intramolecular nucleophilic substitution reaction under the action of a base and optionally under the action of a catalyst (preferably sodium iodide or potassium iodide) to obtain a compound represented by the general formula (IIIA) or a salt thereof,

wherein:

x is a leaving group, preferably halogen, more preferably bromine;

M、R ¹ 、R ^3a l, p and t are as defined in formula (IIIA).

Scheme ten

The preparation method of the compound shown in the general formula (IVA) or the salt thereof comprises the following steps:

(c ') the compound represented by the general formula (IVB') or a salt thereof is subjected to intramolecular nucleophilic substitution reaction under the action of a base and optionally under the action of a catalyst (preferably sodium iodide or potassium iodide) to obtain a compound represented by the general formula (IVA) or a salt thereof,

wherein:

x is a leaving group, preferably halogen, more preferably bromine;

M、R ¹ 、R ^3a m and t are as defined in formula (IVA).

In the reactions of the above steps (a), (c) and (c'), the base includes organic bases including but not limited to triethylamine, pyridine, N-diisopropylethylamine, N-butyllithium, lithium diisopropylamide, sodium acetate, potassium acetate, sodium tert-butoxide, potassium tert-butoxide or 1,8-diazabicycloundecen-7-ene, and inorganic bases including but not limited to sodium hydride, potassium phosphate, sodium carbonate, potassium carbonate, cesium carbonate, sodium hydroxide, lithium hydroxide and potassium hydroxide; a base as described in the reaction of steps (a) and (c'), preferably potassium carbonate; a base as described in step i in step (c), preferably triethylamine; the base used in step ii in step (c) is preferably potassium tert-butoxide.

In the above reaction of step (b), the reducing agent includes, but is not limited to, lithium aluminum hydride, lithium borohydride, sodium borohydride, potassium borohydride, sodium borohydride-ZnCl ₂ Sodium borohydride-AlCl ₃ Potassium borohydride-ZnCl ₂ Potassium borohydride-AlCl ₃ Sodium metal and alcohol; lithium aluminum hydride is preferred.

The reaction of the above scheme is preferably carried out in a solvent including, but not limited to: ethylene glycol dimethyl ether, acetic acid, methanol, ethanol, acetonitrile, N-butanol, toluene, tetrahydrofuran, dichloromethane, petroleum ether, ethyl acetate, N-hexane, dimethyl sulfoxide, 1,4-dioxane, water, N-dimethylformamide, N-dimethylacetamide, 1,2-dibromoethane, and mixtures thereof.

Detailed Description

The following examples are presented to further illustrate the present disclosure, but are not intended to limit the scope of the present disclosure.

Examples

The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) of 10 ^-6 The units in (ppm) are given. NMR was measured using a Bruker AVANCE NEO 500M nuclear magnetic spectrometer using deuterated dimethyl sulfoxide (DMSO-d) as the solvent ₆ ) Deuterated chloroform (CDCl) ₃ ) Deuterated methanol (CD) ₃ OD), internal standard Tetramethylsilane (TMS).

For MS measurement, agilent 1200/1290DAD-6110/6120Quadrupole MS LC-MS (manufacturer: agilent, MS model: 6110/6120Quadrupole MS), waters ACQuority UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuority Qda Detector/waters SQ Detector), and THERMO Umate 3000-Q active (manufacturer: THERMO, MS model: THERMO Q active) were used.

High Performance Liquid Chromatography (HPLC) analysis was performed using Agilent HPLC 1200DAD, agilent HPLC 1200VWD and Waters HPLC e2695-2489 HPLC.

Chiral HPLC assay using Agilent 1260DAD HPLC.

High Performance liquid preparation Waters 2767, waters 2767-SQ Detector 2, shimadzu LC-20AP and Gilson-281 preparative chromatographs were used.

Chiral preparation was performed using Shimadzu LC-20AP preparative chromatograph.

The CombiFlash rapid preparation instrument uses CombiFlash Rf200 (TELEDYNE ISCO).

The thin-layer chromatography silica gel plate adopts a cigarette platform yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the thin-layer chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin-layer chromatography separation and purification product is 0.4 mm-0.5 mm.

Silica gel column chromatography generally uses 200-300 mesh silica gel from Futai Huanghai silica gel as a carrier.

Average inhibition rate of kinase and IC ₅₀ The values were determined with a NovoStar microplate reader (BMG, germany).

Known starting materials of the present disclosure may be synthesized using or according to methods known in the art, or may be purchased from companies such as ABCR GmbH & co.kg, acros Organics, aldrich Chemical Company, nephelo Chemical science and technology (Accela ChemBio Inc), dare chemicals, and the like.

In the examples, the reaction can be carried out in an argon atmosphere or a nitrogen atmosphere, unless otherwise specified.

An argon atmosphere or nitrogen atmosphere means that the reaction flask is connected to a balloon of argon or nitrogen with a volume of about 1L.

The hydrogen atmosphere refers to a reaction flask connected with a hydrogen balloon with a volume of about 1L.

The pressure hydrogenation reaction uses a hydrogenation apparatus of Parr 3916EKX type and a hydrogen generator of Qinglan QL-500 type or a hydrogenation apparatus of HC2-SS type.

The hydrogenation reaction was usually evacuated and charged with hydrogen and repeated 3 times.

The microwave reaction was carried out using a CEM Discover-S908860 microwave reactor.

In the examples, the solution means an aqueous solution without specific indication.

In the examples, the reaction temperature is, unless otherwise specified, room temperature and is 20 ℃ to 30 ℃.

The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), a developing solvent used for the reaction, a system of eluents for column chromatography used for purifying compounds and a developing solvent system for thin layer chromatography including: a: n-hexane/ethyl acetate system, B: the volume ratio of the solvent in the dichloromethane/methanol system is adjusted according to the polarity of the compound, and a small amount of basic or acidic reagents such as triethylamine, acetic acid and the like can be added for adjustment.

Example 1

2- ((1H-pyrazol-1-yl) methyl) -13-methoxy-5,6,7,8-tetrahydro-15H-4,9,17-trioxa-14-thia-15,16-diazabenzo [10,11] cyclotrideca [1,2,3-cd ] indene 14,14-dioxide 1

First step of

2-methoxy-6- (methoxymethoxy) benzenesulfinic acid lithium salt 1b

1-methoxy-3- (methoxymethoxy) benzene 1a (6.5g, 37.87mmol, prepared by the method disclosed in "Organic Letters,2005,7,1031-1034") and tetramethylethylenediamine (4.85g, 41.74mmol, adamas) were dissolved in n-hexane (100 mL) and replaced with nitrogen 3 times. The reaction was cooled to 0 ℃ and n-butyllithium (2.67g, 41.68mmol, adamas) was added dropwise. The reaction solution was stirred at 0 ℃ for 0.5 hour. The reaction solution was cooled to-78 ℃ and dried sulfur dioxide gas was introduced for 30 minutes. The reaction mixture was warmed to room temperature and then filtered under reduced pressure, and the filter cake was washed with dehydrated ether (50 mL), collected and dried in vacuo to give the title product 1b (9 g, yield: 99.8%).

Second step of

2-methoxy-6- (methoxymethoxy) benzenesulfonyl chloride 1c

Compound 1b (9g, 37.78mmol) is dissolved in n-hexane (100 mL), cooled to 0 ℃, and sulfuryl chloride (5.1g, 37.78mmol, national drug) is added dropwise under the protection of nitrogen. The reaction solution was warmed to room temperature and stirred for 12 hours. The reaction solution was suction-filtered under reduced pressure, and the cake was washed with n-hexane. The filter cake was dissolved in diethyl ether (200 mL), washed with a saturated sodium chloride solution (20 mL. Times.2), the resulting organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the title product 1c (5.28 g, yield: 52.4%).

¹ H NMR(500MHz,CDCl ₃ )δ7.54(t,1H),6.90(dd,1H),6.73(d,1H),5.35(s,2H),4.01(s,3H),3.58(s,3H)。

The third step

2- (benzyloxy) -4-bromo-6-fluorobenzonitrile 1e

Benzyl alcohol (7.8g, 72.13mmol, guyao) was dissolved in tetrahydrofuran (100 mL), the reaction was cooled to 0 deg.C, and sodium hydride (3.55g, 81.88mmol, 60% pure, guyao) was added. The reaction mixture was stirred at room temperature for 0.5 hour.

4-bromo-2,6-difluorobenzonitrile 1d (15g, 68.81mmol, shaoyuan) was dissolved in tetrahydrofuran (200 mL), the reaction solution was cooled to 0 ℃ and the above solution of sodium phenylmethoxide in tetrahydrofuran was added dropwise. The reaction mixture was stirred at room temperature for 1 hour. The reaction solution was quenched with water (2 mL), followed by drying over anhydrous sodium sulfate, filtration, and concentration of the filtrate under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1e (13 g, yield: 61.7%).

¹ H NMR(500MHz,CDCl ₃ )δ7.49-7.36(m,5H),7.06-6.99(m,2H),5.23(s,2H)。

The fourth step

3- (benzyloxy) -4-cyano-5-fluorobenzoic acid methyl ester 1f

Compound 1e (6.3g, 20.58mmol) was dissolved in 30mL of a mixed solvent of methanol and N, N-dimethylformamide (V: V = 1:1), and 1,1' -bis diphenylphosphinoferrocene palladium dichloride (1.5g, 2.05mmol, adamas), triethylamine (6.2g, 61.27mmol, national medicine) were added in this order. Carbon monoxide was substituted 3 times and the carbon monoxide protective reaction solution was stirred at 80 ℃ for 12 hours. The reaction solution was cooled to room temperature, concentrated under reduced pressure, diluted with ethyl acetate (200 mL), washed with saturated sodium chloride solution (30 mL. Times.5), the resulting organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1f (3.03 g, yield: 51.6%).

¹ H NMR(500MHz,CDCl ₃ )δ7.55–7.34(m,7H),5.30(s,2H),3.98(s,3H)。

The fifth step

3-amino-4- (benzyloxy) benzo [ d ] isoxazole-6-carboxylic acid methyl ester 1g

Compound 1f (3.03g, 10.62mmol), acetohydroxamic acid (2.4g, 31.33mmol, adamas) were dissolved in N, N-dimethylformamide (50 mL), and potassium carbonate (7 g,50.65mmol, national medicine) was added. The reaction solution was stirred at 60 ℃ for 16 hours. The reaction solution was filtered, diluted with ethyl acetate (500 mL), washed with saturated sodium chloride solution (50 mL. Times.5), the resulting organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to obtain 1g of the title product (1.94 g, yield: 61.2%).

MS m/z(ESI):299.1[M+1]。

The sixth step

4- (benzyloxy) -3- ((2-methoxy-6- (methoxymethoxy) phenyl) sulfonamido) benzo [ d ] isoxazole-6-carboxylic acid methyl ester 1h

1g (1.2g, 4.02mmol) of the compound was dissolved in tetrahydrofuran (40 mL) and nitrogen was replaced 3 times, and the reaction mixture was cooled to-40 ℃ and lithium bistrimethylsilylamide (2.0 g,11.95mmol, adamas) was added. After the reaction mixture was stirred at-40 ℃ for 1 hour, compound 1c (1.60g, 6.00mmol) was added, and the reaction mixture was slowly warmed to room temperature and stirred for 16 hours. The reaction was quenched with water (10 mL), extracted with ethyl acetate (100 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1h (637 mg, yield: 30%).

MS m/z(ESI):529.0[M+1]。

Seventh step

methyl 3- ((N-allyl-2-methoxy-6- (methoxymethoxy) phenyl) sulfonamido) -4- (benzyloxy) benzo [ d ] isoxazole-6-carboxylic acid methyl ester 1i

Compound 1h (636mg, 1.20mmol) was dissolved in N, N-dimethylformamide (15 mL), and potassium carbonate (850mg, 6.1503mmol, a national medicine) and allyl bromide (720mg, 5.95mmol, adamas) were added. The reaction solution was stirred at 50 ℃ for 16 hours. The reaction solution was quenched with water (10 mL), extracted with ethyl acetate (50 mL. Times.3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1i (568 mg, yield: 83%).

MS m/z(ESI):569.0[M+1]。

The eighth step

3- ((N-allyl-2-hydroxy-6-methoxyphenyl) sulfonamido) -4- (benzyloxy) benzo [ d ] isoxazole-6-carboxylic acid methyl ester 1j

Compound 1i (568mg, 998. Mu. Mol) was dissolved in methylene chloride (40 mL), nitrogen gas was replaced with 3 times, the reaction solution was cooled to-78 ℃ and boron trichloride (177mg, 1.51mmol, adamas) was added. The reaction solution was stirred at-78 ℃ for 0.5 hour. The reaction was quenched by addition of saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (100 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1j (435 mg, yield: 83%).

MS m/z(ESI):525.0[M+1]。

The ninth step

3- ((N-allyl-2- (4-bromobutoxy) -6-methoxyphenyl) sulfonylamino) -4- (benzyloxy) benzo [ d ] isoxazole-6-

Carboxylic acid methyl ester 1k

Compound 1j (437mg, 833. Mu. Mol) was dissolved in N, N-dimethylformamide (10 mL), and potassium carbonate (500mg, 3.61mmol, wako pure chemical industries, ltd.) and 1,4-dibromobutane (670mg, 2.48mmol, adamas) were added. The reaction solution was stirred at 50 ℃ for 1 hour. The reaction solution was filtered, diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (20 mL × 5), the resulting organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system a to give the title product 1k (484 mg, yield: 88%).

MS m/z(ESI):658.9[M+1]。

The tenth step

3- ((N-allyl-2- (4-bromobutoxy) -6-methoxyphenyl) sulfonamido) -4-hydroxybenzo [ d ] isoxazole-6-carboxylic acid methyl ester 1l

Compound 1k (484mg, 733. Mu. Mol) was dissolved in methylene chloride (15 mL), nitrogen was replaced 3 times, the reaction mixture was cooled to-78 ℃ and boron trichloride (601mg, 5.12mmol, adamas) was added. The reaction solution was stirred at-78 ℃ for 4 hours. The reaction was quenched by addition of saturated sodium bicarbonate solution (10 mL), extracted with ethyl acetate (100 mL. Times.2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1l (417 mg, yield: 99%).

MS m/z(ESI):568.9[M+1]。

The eleventh step

15-allyl-13-methoxy-5,6,7,8-tetrahydro-15H-4,9,17-trioxa-14-thia-15,16-diazabenzo [10,11] cyclotrideca [1,2,3-cd ] indene-2-carboxylic acid methyl ester 14,14-dioxide 1m

Compound 1l (418mg, 734. Mu. Mol) was dissolved in dimethyl sulfoxide (50 mL), and potassium carbonate (202mg, 1.46mmol, wako pure chemical industries, ltd.) and sodium iodide (48mg, 320. Mu. Mol, adamas) were added. The reaction solution was stirred at 45 ℃ for 2 hours. The reaction solution was filtered, the obtained filtrate was diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (20 mL. Times.5), the obtained organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography with eluent system A to obtain the title product 1m (309 mg, yield: 86%). MS m/z (ESI) 489.0[ m +23].

The twelfth step

15-allyl-2- (hydroxymethyl) -13-methoxy-5,6,7,8-tetrahydro-15H-4,9,17-trioxa-14-thia-15,16-diazabenzo [10,11] cyclotrideca [1,2,3-cd ] indene 14,14-dioxide 1n

Compound 1m (309mg, 632. Mu. Mol) was dissolved in dry tetrahydrofuran (10 mL), nitrogen was replaced 3 times, the reaction was cooled to-15 ℃ and lithium aluminum hydride (21mg, 619. Mu. Mol, adamas) was added. The reaction solution was stirred at-15 ℃ for 1 hour. The reaction was quenched with water (1 mL), dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1n (275 mg, yield: 94%).

MS m/z(ESI):461.0[M+1]。

Thirteenth step

2- ((1H-pyrazol-1-yl) methyl) -15-allyl-13-methoxy-5,6,7,8-tetrahydro-15H-4,9,17-trioxa-14-thia-15,16-diazabenzo [10,11] cyclotrideca [1,2,3-cd ] indene 14,14-dioxide 1o

Pyrazole (214mg, 3.14mmol, adamas) was dissolved in dry N, N-dimethylformamide (11 mL), the reaction was cooled to 0 ℃ and potassium tert-butoxide (345mg, 3.07mmol, shaoyuan) was added, the reaction was warmed to room temperature and stirred for 1 hour, and the reaction was ready for use.

Compound 1n (275mg, 597. Mu. Mol) was dissolved in dichloromethane (10 mL), the reaction was cooled to 0 ℃ and triethylamine (302mg, 2.98mmol, gumbo) and methanesulfonyl chloride (210mg, 1.83mmol, gumbo) were added and the reaction was warmed to room temperature and stirred for 1 hour. The reaction solution was cooled to 0 ℃ and the above-mentioned alkaline reaction solution containing pyrazole was added dropwise. After the addition, the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction solution was quenched with water (10 mL), diluted with ethyl acetate (100 mL), washed with saturated sodium chloride solution (20 mL. Times.2), the resulting organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system A to give the title product 1o (221 mg, yield: 72.6%).

MS m/z(ESI):511.0[M+1]

Fourteenth step

Compound 1o (214mg, 3.14mmol) was dissolved in dry tetrahydrofuran (8 mL), 1,3-dimethylbarbituric acid (203mg, 1.30mmol, adamas) and tetrakis (triphenylphosphine) palladium (205mg, 177. Mu. Mol, adamas) were added, and the reaction was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (Welch Ultimate XB-C18 μm 30X 150mM; mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile =25% -41% (16 min), flow rate: 30 mL/min) to give the title product 1 (80 mg, yield: 39.2%). MS m/z (ESI) 471.1[ 2] M + 1.

¹ H NMR(500MHz,CDCl ₃ )δ9.06(s,1H),7.56(d,1H),7.43(d,1H),7.34(t,1H),6.79(s,1H),6.62(d,1H),6.55(d,1H),6.44(s,1H),6.31(t,1H),5.36(s,2H),4.23(dt,4H),3.90(s,3H),2.16(ddd,4H)。

Example 2

4- ((1H-pyrazol-1-yl) methyl) -13-methoxy-7,8-dihydro-15H-2,6,9-trioxa-14-thia-1,15-diazabenzo [8,9] cycloundeceno [1,2,3-cd ] indene 14,14-dioxide 2

The synthetic route of example 1 was followed to replace the starting compound 1,4-dibromobutane in the ninth step with the starting compound 1,2-dibromoethane (Shaoyuan) to give the title compound 2 (24 mg).

MS m/z(ESI):443.0[M+1]。

¹ H NMR(500MHz,DMSO)δ7.85(s,1H),7.49(s,1H),7.15(t,1H),6.82(s,1H),6.67-6.64(m,2H),6.54(d,1H),6.29(s,1H),6.07(br,1H),5.37(s,2H),4.36-4.34(m,2H),4.15-4.13(m,2H),3.71(s,3H)。

Example 3

2- ((1H-pyrazol-1-yl) methyl) -12-methoxy-6,7-dihydro-5H, 14H-4,8,16-trioxa-13-thia-14,15-diazabenzo [9,10] cyclododeca [1,2,3-cd ] indene 13,13-dioxide 3

The procedure of example 1 was followed to replace the starting compound 1,4-dibromobutane in the ninth step with 1,3-dibromopropane (Shaoyuan) to give the title compound 3 (36 mg).

MS m/z(ESI):457.0[M+1]。

¹ H NMR(500MHz,DMSO)δ8.12(br,1H),7.87(s,1H),7.49(s,1H),7.45(t,1H),6.87(s,1H),6.78(d,1H),6.78-6.73(m,2H),6.29(s,1H),5.42(s,2H),4.54-4.52(m,2H),4.32-4.31(m,2H),3.81(s,3H),2.28-2.24(m,2H)。

Example 4

2- ((1H-pyrazol-1-yl) methyl) -14-methoxy-6,7,8,9-tetrahydro-5H, 1693H-4,10,18-trioxa-15-thia-16,17-diazabenzo [11,12] cyclotetradecano [1,2,3-cd ] indene 15,15-dioxide 4

Using the synthetic route of example 1, the starting compound 1,4-dibromobutane of the ninth step was replaced with the starting compound 1,5-dibromopentane (Shaoyuan) to afford the title compound 4 (18 mg).

MS m/z(ESI):485.0[M+1]。

¹ H NMR(500MHz,DMSO)δ8.54(br,1H),7.88(s,1H),7.53-7.50(m,2H),6.85-6.79(m,4H),6.30(s,1H),5.44(s,2H),4.36-4.34(m,2H),4.13-4.12(m,2H),3.87(s,3H),1.89-1.88(m,2H),1.79-1.75(m,2H),1.68-1.64(m,2H)。

Example 5

2- ((1H-pyrazol-1-yl) methyl) -14-fluoro-6,7,8,9-tetrahydro-5H, 1697-4,10,18-trioxa-15-thia-16,17-diazabenzo [11,12] cyclotetradeca [1,2,3-cd ] indene 15,15-dioxide 5

First step of

1-fluoro-3- (methoxymethoxy) benzene 5b

3-fluorophenol 5a (70g, 0.63mol, bi De) was dissolved in 500mL of acetonitrile under ice bath, and anhydrous potassium carbonate (130g, 0.94mol, national medicine) was added. Bromomethylmethylether (78g, 0.63mol, adamas) was then added dropwise and the reaction was carried out at room temperature for 12 hours. The reaction solution was filtered, the filtrate was concentrated under reduced pressure, 200mL of saturated sodium carbonate solution was added, extraction was performed with n-heptane (100 mL. Times.3), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution (100 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title product 5b (63.0 g), which was directly subjected to the next reaction without purification.

Second step of

2-fluoro-6- (methoxymethoxy) benzenesulfinic acid lithium 5c

Crude compound 5b (50g, 0.32mol), tetramethylethylenediamine (41g, 0.35mol, adamas) was dissolved in 700mL of n-hexane at-10 ℃ and n-butyllithium (141mL, 0.35mol,2.5M in-hexane, adamas) was added dropwise. Then the temperature is reduced to-78 ℃, sulfur dioxide is introduced and the reaction lasts for 1 hour. The reaction was filtered and the filter cake collected and dried in vacuo to give the crude title product 5c (72 g), which was directly used in the next reaction without purification.

The third step

2-fluoro-6- (methoxymethoxy) benzenesulfonyl chloride 5d

Crude compound 5c (72g, 0.32mol) was dissolved in 700mL of n-hexane under ice-cooling, and sulfuryl chloride (41.3g, 0.32mol, adamas) was slowly added dropwise and reacted for 1 hour. The reaction was filtered and the filtrate was concentrated under reduced pressure to give the crude title product 5d (17 g), which was carried on to the next reaction without purification.

The fourth step

2- (benzyloxy) -6-fluoro-4- (hydroxymethyl) benzonitrile 5e

Compound 1f (10g, 35.05mmol) was dissolved in 60mL of tetrahydrofuran under ice-cooling, and lithium borohydride (1.61g, 70.10mmol, adamas) was dissolved in 10mL of tetrahydrofuran and added dropwise to the reaction solution, followed by reaction at 50 ℃ for 1 hour. To the reaction system was added 50mL of water, 1M hydrochloric acid was added dropwise to a reaction solution pH of 5-6, extraction was performed with ethyl acetate (100 mL × 3), organic phases were combined, the organic phase was washed with a saturated sodium chloride solution (100 mL × 3), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a crude title compound 5e (9 g), which was directly subjected to the next reaction without purification.

MS m/z(ESI):258.1[M+1]。

The fifth step

4- ((1H-pyrazol-1-yl) methyl) -2- (benzyloxy) -6-fluorobenzonitrile 5f

Crude compound 5e (9 g, 34.98mmol), pyrazole (2.86g, 41.98mmol, adamas) and tributylphosphine (8.50g, 41.98mmol, adamas) were dissolved in 100mL tetrahydrofuran under ice-bath. Azodicarbonamide (7.50g, 43.58mmol, obtained) was dissolved in 100mL tetrahydrofuran and added dropwise to the reaction mixture and reacted at room temperature for 2 hours. To the reaction system, 20mL of water was added, part of tetrahydrofuran was removed by concentration under reduced pressure, extracted with ethyl acetate (40 mL × 3), the organic phases were combined, the organic phase was washed with a saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain the title product 5f (7 g, 65.1%).

MS m/z(ESI):308.1[M+1]。

The sixth step

5g of 6- ((1H-pyrazol-1-yl) methyl) -4- (benzyloxy) benzo [ d ] isoxazol-3-amine

Compound 5f (7g, 22.80mmol), acetohydroxamic acid (5.14g, 68.47mmol, bi), tetramethylguanidine (15.80g, 137.18mmol, bi) were dissolved in 100mL acetonitrile and 12mL water and reacted at 60 ℃ with stirring for 12 hours. To the reaction system was added 20mL of water, concentrated under reduced pressure to remove part of acetonitrile, extracted with ethyl acetate (30 mL × 3), the organic phases were combined, washed with saturated sodium chloride solution (20 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to obtain 5g (4.80g, 65.8%) of the title product.

MS m/z(ESI):321.1[M+1]。

Seventh step

N- (6- ((1H-pyrazol-1-yl) methyl) -4- (benzyloxy) benzo [ d ] isoxazol-3-yl) -2-fluoro-6- (methoxymethoxy) benzenesulfonamide for 5H

5g (5 g, 15.61mmol) of the compound was dissolved in 130mL of tetrahydrofuran under ice-cooling, and bis (trimethylsilyl) aminolithium (19.5 mL,19.51mmol,1M tetrahydrofuran solution, an Naiji) was added and reacted for 1 hour. Compound 5d (5.15g, 20.29mmol) was dissolved in 30mL of tetrahydrofuran and added dropwise to the reaction mixture, and the mixture was reacted at room temperature for 1 hour. To the reaction system was added 20mL of water, concentrated under reduced pressure to remove part of the tetrahydrofuran, extracted with ethyl acetate (40 mL. Times.3), the organic phases combined, washed with saturated sodium chloride solution (20 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate concentrated under reduced pressure to give the crude title product 5h (2.10 g), which was directly subjected to the next reaction without purification.

MS m/z(ESI):539.1[M+1]。

Eighth step

N- (6- ((1H-pyrazol-1-yl) methyl) -4- (benzyloxy) benzo [ d ] isoxazol-3-yl) -N-allyl-2-fluoro-6- (methoxymethoxy) benzenesulfonamide 5i

The crude compound (5 h, 2.10g, 3.90mmol) was dissolved in 20mL of N, N-dimethylformamide, and potassium carbonate (2.16g, 15.63mmol, guo Yao) and allyl bromide (1.89g, 15.63mmol, adamas) were added and the reaction was stirred at 50 ℃ for 1 hour. The reaction solution was filtered, 100mL of water was added to the filtrate, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, the organic phase was washed with a saturated sodium chloride solution (30 mL × 2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 5i (1.50g, 66.5%).

MS m/z(ESI):579.2[M+1]。

The ninth step

N- (6- ((1H-pyrazol-1-yl) methyl) -4- (benzyloxy) benzo [ d ] isoxazol-3-yl) -N-allyl-2-fluoro-6-hydroxybenzenesulfonamide 5j

Compound 5i (1.50g, 2.59mmol) was dissolved in 20mL of methanol, and 13mL of a solution of 4M hydrogen chloride in 1,4-dioxane was added and the reaction was stirred at 40 ℃ for 1 hour. The reaction was concentrated under reduced pressure to give crude title product 5j (1.42 g), which was carried on to the next reaction without purification.

MS m/z(ESI):535.1[M+1]。

The tenth step

N- (6- ((1H-pyrazol-1-yl) methyl) -4- (benzyloxy) benzo [ d ] isoxazol-3-yl) -N-allyl-2- ((5-bromopentyl) oxy) -6-fluorobenzenesulfonamide 5k

The crude compound 5j (300mg, 0.56mmol), potassium carbonate (232.58mg, 1.69mmol, national medicine), 1,5-dibromopentane (387.64mg, 1.69mmol, bi) were dissolved in 15mL of dimethyl sulfoxide and reacted for 1 hour with microwave stirring at 50 ℃. The reaction solution was filtered, 20mL of water was added to the filtrate, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, the organic phase was washed with saturated sodium chloride solution (10.0 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give the crude title compound 5k (260 mg) which was directly subjected to the next reaction without purification.

MS m/z(ESI):683.1[M+1]。

The eleventh step

N- (6- ((1H-pyrazol-1-yl) methyl) -4-hydroxybenzo [ d ] isoxazol-3-yl) -N-allyl-2- ((5-bromopentyl) oxy) -6-fluorobenzenesulfonamide 5l

Crude compound 5k (260mg, 0.38mmol) was dissolved in 8mL of dichloromethane, cooled to-30 deg.C, boron tribromide (4.6 mL,4.60mmol,1M dichloromethane solution, adamas) was added dropwise, and the reaction was stirred for 1 hour. To the reaction solution was added 20mL of saturated sodium bicarbonate solution, extracted with dichloromethane (10 mL. Times.3), the organic phases were combined, washed with saturated sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give 5L (230 mg) of the crude title compound, which was directly subjected to the next reaction without purification. MS m/z (ESI) 593.1[ 2], [ M +1].

The twelfth step

2- ((1H-pyrazol-1-yl) methyl) -16-allyl-14-fluoro-6,7,8,9-tetrahydro-5H, 1693H-4,10,18-trioxa-15-thia-16,17-diazabenzo [11,12] cyclotetradecano [1,2,3-cd ] indene 15,15-dioxide 5m

5l (230mg, 0.39mmol) of the crude compound was dissolved in 6mL of dimethyl sulfoxide, and potassium carbonate (263mg, 1.16mmol, chinese medicine) was added thereto, followed by stirring at 45 ℃ for 1.5 hours. To the reaction system was added 20mL of water, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, the organic phase was washed with a saturated sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography with eluent system B to give the title product 5m (130mg, 65.5%).

MS m/z(ESI):513.2[M+1]。

Thirteenth step

2- ((1H-pyrazol-1-yl) methyl) -14-fluoro-6,7,8,9-tetrahydro-5H, 1697-4,10,18-trioxa-15-thia-16,17-diazabenzo [11,12] cyclotetradecano [1,2,3-cd ] indene 15,15-dioxide 5

Compound 5m (130mg, 0.25mmol) was dissolved in 10mL tetrahydrofuran, 1,3-dimethylbarbituric acid (130mg, 0.82mmol, adamas), tetrakis (triphenylphosphine) palladium (167mg, 0.11mmol, bi obtained) were added, and the reaction was stirred at 40 ℃ for 1 hour. To the reaction system was added 20mL of water, extracted with ethyl acetate (10 mL. Times.3), the organic phases were combined, the organic phase was washed with a saturated sodium chloride solution (10 mL. Times.2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the resulting residue was purified by high performance liquid chromatography (YMC Triart-Exrs Prep 5. Mu.m 30. Times.150 mM; mobile phase: A-aqueous phase (10 mM ammonium bicarbonate): B-acetonitrile =23% -38% (15 min), flow rate: 30 mL/min) to give the title product 5 (35mg, 29.5%).

MS m/z(ESI):473.1[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ8.94(br,1H),7.88-7.84(m,1H),7.60(s,1H),7.49(s,1H),7.04-6.95(m,2H),6.85-6.76(m,2H),6.29-6.28(m,1H),5.42(s,2H),4.39-4.28(m,2H),4.22-4.06(m,2H),1.89-1.73(m,4H),1.69-1.53(m,2H)。

Example 6

2- ((1H-pyrazol-1-yl) methyl) -13-fluoro-5,6,7,8-tetrahydro-15H-4,9,17-trioxa-14-thia-15,16-diazabenzo [10,11] cyclotrideca [1,2,3-cd ] indene 14,14-dioxide 6

Using the synthetic route of example 5, the starting compound 1,5-dibromopentane from the tenth step was replaced with the starting compound 1,4-dibromobutane (obtained), to give the title compound 6 (50 mg).

MS m/z(ESI):459.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ9.47(s,1H),7.86(d,1H),7.56(s,1H),7.49(d,1H),7.05(d,1H),6.89(t,1H),6.85(s,1H),6.76(s,1H),6.30(t,1H),5.41(s,2H),4.26(d,4H),2.08(s,4H)。

Example 7

2- ((1H-pyrazol-1-yl) methyl) -5,6,7,8-tetrahydro-15H-4,9,17-trioxa-14-thia-15,16-diazabenzo [10,11] cyclotrideca [1,2,3-cd ] indene 14,14-dioxide 7

The procedure of example 5 was followed, substituting the starting compound 3-fluorophenol in the first step with the starting compound phenol (Adamas) and the starting compound 1,5-dibromopentane in the tenth step with the starting compound 1,4-dibromobutane (Bi) to give the title compound 7 (30 mg).

MS m/z(ESI):441.0[M+1]。

¹ H NMR(500MHz,DMSO-d ₆ )δ9.29(s,1H),7.85(d,1H),7.77(dd,1H),7.61-7.54(m,1H),7.48(d,1H),7.23(d,1H),7.03(t,1H),6.81(s,1H),6.72(s,1H),6.29(d,1H),5.40(s,2H),4.24(dt,4H),2.09(td,4H)。

Example 8

2- ((1H-pyrazol-1-yl) methyl) -6,7,8,9-tetrahydro-5H, 1693H-4,10,18-trioxa-15-thia-16,17-diazabenzo [11,12] cyclotetradecano [1,2,3-cd ] indene 15,15-dioxide 8

Using the synthetic route of example 5, the starting compound 3-fluorophenol in the first step was replaced with the starting compound phenol (Adamas) to give the title compound 8 (30 mg).

MS m/z(ESI):455.0[M+1]。

¹ H NMR(500MHz,CDCl ₃ )δ8.24(s,1H),8.15-8.13(m,1H),7.61-7.47(m,2H),7.08-7.03(m,1H),6.97-6.94(m,1H),6.77(s,1H),6.43-6.35(m,2H),5.38(s,2H),4.25-4.16(m,4H),2.02-1.88(m,4H),1.83-1.78(m,2H)。

Example 9

2- ((1H-pyrazol-1-yl) methyl) -14-methoxy-5,6,8,9-tetrahydro-16H-4,7,10,18-tetraoxa-15-thia-16,17-diazabenzo [11,12] cyclotetradecano [1,2,3-cd ] indene 15,15-dioxide 9

Using the synthetic route of example 1, the starting compound 1,4-dibromobutane from the ninth step was replaced with the starting compound 2,2' -dibromodiethyl ether (Shaosuan) to afford the title compound 9 (20 mg).

MS m/z(ESI):487.0[M+1]。

1H NMR(500MHz,CDCl ₃ )δ8.50(br,1H),7.55-7.53(m,1H),7.42-7.40(m,1H),7.39-7.36(m,1H),6.80(s,1H),6.68-6.66(m,1H),6.50-6.48(m,1H),6.43(s,1H),6.30-6.29(m,1H),5.35(s,2H),4.27-4.25(m,2H),4.16-4.14(m,2H),3.99-3.96(m,5H),3.92-3.90(m,2H)。

Biological evaluation

The present disclosure is further described below in conjunction with test examples, which are not meant to limit the scope of the present disclosure.

Test example 1 inhibition of human KAT6 enzyme by the Compound of the present disclosure (radioisotope method)

Experimental materials and instruments

Kat6a (Chempartner subscription)

2.KAT6B(Active motif,Cat.No.81224)

3.KAT5(BPS,Cat.No.79422)

4.KAT7(Active motif,Cat.No.31889)

5. Recombinant KAT8/MYST1 protein (Active Motif, cat. No. 81925)

6. Acetyl coenzyme A, [ Acetyl-3H ] (PERKIN ELMER, cat.No.NET290250UC)

7. Acetyl coenzyme A (CAYMAN, cat. No. 16160)

H4 (1-30) (GL biochem custom)

9. 384-well Flashplate(Perkin Elmer,Cat.No.SMP410A001PK)

10. Mangosteen (MCE, cat. No. HY-107569)

11. Lacqueric acid (MCE, cat. No. HY-N2020)

Echo 550 pipetting system (Labcyte Echo 550)

13. Micro plate counter (PERKIN ELMER Microbeta 2)

Second, experimental procedure

(one) reagent preparation

1X assay buffer 10mM Tris-HCl (pH 8.0), 0.01% Tween-20, 1mM DTT.

KAT enzyme solution: the final concentrations were prepared in 1 × assay buffer, see table below.

A mixed substrate of [3H ] -Ac-CoA and H4 peptide: the 1 × assay buffer was prepared with final concentrations (see Table below) of [3H ] -Ac-CoA and H4 peptide, respectively, and mixed.

d. A compound: transferring the 100% DMSO-containing compound to the reaction plate using an Echo pipetting system, the final DMSO content being 1%.

(II) Experimental procedure

a. Transfer 10. Mu.L of enzyme solution or low control buffer to the reaction plate.

b. Incubate for 15 minutes at room temperature.

c. The reaction was initiated by adding 10. Mu.L of a mixed solution of [3H ] -Ac-CoA and H4 peptide per well.

KAT6a, KAT6B, KAT5, KAT7 and KAT8 were reacted for 20 minutes, 2 hours, 45 minutes and 60 minutes, respectively.

e. Preparation of stop solution: stop solutions were prepared by adding cold Ac-COA to the 1 × assay buffer.

f. The reaction was stopped by adding 10. Mu.L of stop solution per well.

g. Transfer 25. Mu.L per well from the reaction plate to 384-well Flashplate.

h. Incubate at room temperature for at least 1 hour.

i. Read the plate with Microbeta 2.

3. Data analysis

The inhibition rate was obtained by introducing the data into Excel using equation (1). Importing the inhibition rate data into XL-Fit, and calculating IC according to formula (2) ₅₀ 。

In the formula (1), inh% = (Max-Signal)/(Max-Min) × 100.

Formula (2): y = Bottom + (Top-Bottom)/(1 + (IC) ₅₀ /X) HillSlope), wherein Y is the inhibition rate and X is the compound concentration.

TABLE 1 IC for inhibition of human KAT6 enzyme by the disclosed compounds ₅₀ Value of

And (4) conclusion: the disclosed compounds have good selective inhibition on KAT 6.

Test example 2 KAT6 enzyme Activity detection (AlphaScreen method)

1. Reagent and apparatus

Kat6a (Chempartner subscription)

2. Ovalbumin (Sigma-Aldrich, A5378-5G)

3.2M Tris-HCl solution, pH7.8, sterile (Bio-worker B548140-0500)

4.5M NaCl solution (Bio-worker, B548121-0100)

5.EDTA(0.5M),pH 8.0,RNase-free(Thermofisher,AM9260G)

6. Tween-20 (raw, A100777-0500)

7.DTT,1M(Invitrogen,P2325)

8. Acetyl coenzyme A (CAYMAN, cat. No. 16160)

9.Recombinant Histone H3.1 biotinylated(Human)(Active Motif 31696)

10.AlphaPlate-384,Light gray(Perkin Elmer,Cat.No.6005350)

11. Lacqueric acid (MCE, cat. No. HY-N2020)

12.AlphaScreen Streptavidin Donor beads 5mg(PerkinElmer,6760002)

13.AlphaScreen Protein A Acceptor beads,5mg(PerkinElmer,6760137M)

14. Acetylated lysine antibody #9441 (CST 9441S)

PHERA star microplate reader (BMG labtech)

2. Experimental methods

1. Reagent preparation

1X assay buffer 100mM Tris-HCl, pH7.8;15mM NaCl;1mM EDTA;0.01% tween-20; 1mM DTT;0.01% m/v egg white protein.

Kat enzyme solution: the final concentration was 1.25nM in 1 × assay buffer.

Ac-CoA and H3 mixed substrate: 1 × assay buffer A mixed substrate of Ac-CoA at a final concentration of 1000nM and H3 at a final concentration of 55nM was prepared.

d. A compound: starting concentration 100. Mu.M, 3-fold dilution, 10 concentration gradients. All concentrations of compounds were diluted 83-fold with 1 × assay buffer for use.

e. Detection reagent: 1 × assay buffer solution AlphaScreen Protein A Acceptor beads with a final concentration of 8 ng/. Mu.L, alphaScreen Streptavidin Donor beads with a final concentration of 8 ng/. Mu.L, acetylated lysine antibody 1, 1500 dilution, 100. Mu.M Rhus acid.

2. Experimental procedure

A.384 well plates, 3. Mu.L of the prepared enzyme solution was added to each well, and 3. Mu.L of 1 × assay buffer was added to each well in columns 23 and 24 (Min).

b. Add 3. Mu.L compound solution per well, min add 3. Mu.L buffer per well; columns 1 and 2 (Max) were controlled by adding 3. Mu.L of DMSO solution per well. Centrifuging, mixing uniformly and shaking for 2 minutes; incubate for 15 minutes at room temperature.

c. Add 6. Mu.L Ac-CoA and H3 mixed substrate to each well, centrifuge, mix well and shake for 2 minutes, incubate for 20 minutes at room temperature.

d. Add 6. Mu.L of assay reagent to each well, centrifuge, mix well and shake for 2 minutes, incubate for 120 minutes at room temperature, and protect from light.

e. The plate is read by the microplate reader and the AlphaScreen counts values are recorded.

Graph software mapping, calculating compound IC ₅₀ The value is obtained.

TABLE 2 IC inhibition of human KAT6 enzyme by the disclosed compounds ₅₀ Value of

And (4) conclusion: the disclosed compounds have an inhibitory effect on KAT 6.

Test example 3 pharmacokinetic evaluation

1. SD rat test

1. Abstract

The drug concentrations in plasma of SD rats at different times after gavage (i.g.)/intravenous injection (i.v.) administration of the compound of example 1 and the compound of example 4 were measured by LC/MS method using SD rats as test animals. The pharmacokinetic behavior of the compounds of the disclosure in SD rats was studied and their pharmacokinetic profile was evaluated.

2. Test protocol

2.1 test drugs

The compound of example 1 and the compound of example 4.

2.2 test animals

16 SD rats, half male and female, were evenly divided into 4 groups, provided by Zhejiang Weitonglihua laboratory animal technology, inc. After fasting overnight, the administration was by gavage and intravenous injection, respectively.

2.3 pharmaceutical formulation

A certain amount of the compound of example 1 and the compound of example 4 are weighed respectively, and 5% DMSO +5% Tween 80+90% physiological saline is added to prepare a colorless clear solution (gavage group) of 0.2mg/mL and a colorless clear solution (intravenous group) of 0.2 mg/mL.

2.4 administration of drugs

The intragastric administration group: the dose was 2.0mg/kg and the volume was 10.0mL/kg.

Group for intravenous administration: the dose was 1.0mg/kg and the volume was 5.0mL/kg.

3. Operation of

And (3) intragastric administration group: 0.1mL of blood was collected from the orbit at 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0, 11.0, and 24.0 hours before and after administration, and the blood was placed in an EDTA-K2 anticoagulation tube, centrifuged at 10000rpm for 1 minute (4 ℃), plasma was separated within 1 hour, and the sample was stored at-20 ℃. The blood collection to centrifugation process is operated under ice bath condition. Food was consumed 2 hours after dosing.

Group for intravenous administration: blood was collected before administration and 5 minutes after administration at 0.25, 0.5, 1.0, 2.0, 4.0, 8.0, 11.0 and 24 hours, and the group was treated with intragastric administration.

Determination of the content of the test compounds in the plasma of SD rats after administration of drugs at different concentrations: SD rat plasma samples were taken at 25. Mu.L each at time post-dose, 25. Mu.L camptothecin (100 ng/mL) was added to each sample, and the protein was precipitated with 200. Mu.L acetonitrile, vortex mixed for 5 minutes, and centrifuged at 3700rpm for 10 minutes. mu.L of the supernatant was taken, 30. Mu.L of water was added, vortexed for 5 minutes, and 5. Mu.L of the sample was injected for LC/MS/MS analysis.

4. Pharmacokinetic parameter results

TABLE 3 pharmacokinetic parameters of Compounds of the disclosure

And (4) conclusion: the compound disclosed by the invention has the advantages of large blood concentration, high exposure, low clearance rate, long half-life period and pharmacokinetic advantage in SD rats.

Claims

1. A compound of the general formula (I) or a pharmaceutically acceptable salt thereof:

wherein:

ring a is selected from cycloalkyl, heterocyclyl, aryl and heteroaryl;

R ¹ And R ² The same or differentAnd are each independently selected from the group consisting of hydrogen, alkyl, alkoxy, hydroxyalkyl, haloalkyl, haloalkoxy, alkenyl, alkynyl, halogen, hydroxy, cyano, nitro, oxo, cycloalkyl, heterocyclyl, aryl, heteroaryl, -OR ³ 、-C(O)R ⁴ 、-C(O)OR ⁴ 、-OC(O)R ⁴ 、-NHC(O)OR ⁴ 、-NR ⁵ R ⁶ 、-C(O)NR ⁵ R ⁶ 、-S(O) ₂ R ⁴ and-S (O) ₂ NR ⁵ R ⁶ (ii) a Wherein said alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more R ^A Substituted;

L ₁ and L ₂ Are the same or different and eachIndependently is absent or- (CR) ^c R ^d ) _n -；

or, one or more R ^a And R ^b Together with the same carbon atom to which they are attached form a 3-to 8-membered cycloalkyl group or a 3-to 8-membered heterocyclyl group, wherein the 3-to 8-membered heterocyclyl group contains one or more of N, O or S (O) _r And said 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkyl, alkoxy, haloalkyl, heterocyclylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, hydroxyalkyl, alkenyl, alkynyl, haloalkoxy, halogen, cyano, amino, nitro, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or, any two R ^a Together with the different carbon atoms to which they are each attached form a 3-to 8-membered cycloalkyl or 3-to 8-membered heterocyclyl group, wherein one or more of N, O or S (O) are contained within the 3-to 8-membered heterocyclyl group _r And said 3-to 8-membered cycloalkyl and 3-to 8-membered heterocyclyl are each independently optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkyl, alkoxy, haloalkyl, heterocyclylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, hydroxyalkyl, alkenyl, alkynyl, haloalkoxy, halogen, cyano, amino, nitro, oxo, cycloalkyl, heterocyclyl, aryl, and heteroaryl;

R ^e and R ^k Are the same or different and are each independently selected from the group consisting of a hydrogen atom, an alkenyl group, an alkynyl group, an alkyl group, a haloalkyl group, a hydroxyalkyl group, a cycloalkyl group, a heterocyclic group, an aryl group, and a heteroaryl group;

R ⁴ 、R ^f and R ^f1 Are the same or different and are each independently selected from the group consisting of hydrogen atoms, alkenyl groups, alkynyl groups, alkyl groups, haloalkyl groups, hydroxyalkyl groups, cycloalkyl groups, heterocyclyl groups, aryl groups, and heteroaryl groups; wherein said alkenyl, alkynyl, alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl are each independently optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkyl, alkoxy, haloalkyl, heterocyclylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, hydroxyalkyl, alkenyl, alkynyl, haloalkoxy, halogen, cyano, amino, nitro, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

or, R ⁵ And R ⁶ Together with the linking N atom form a 3-to 8-membered heterocyclic group, or R ^g And R ^h Together with the N atom to which they are attached form a 3-to 8-membered heterocyclic group, or R ^g1 And R ^h1 Together with the N atom to which they are attached form a 3-to 8-membered heterocyclic group containing one or more of N, O or S (O) _r Said heterocyclyl being optionally substituted with one or more substituents selected from the group consisting of hydroxy, alkyl, alkoxy, haloalkyl, heterocyclylalkyl, heteroarylalkyl, cycloalkyloxy, heterocyclyloxy, hydroxyalkyl, alkenyl, alkynyl, haloalkoxy, halogen, cyano, amino, nitro, oxo, cycloalkyl, heterocyclyl, aryl and heteroaryl;

m is selected from 1,2,3, 4, 5,6,7,8, 9 and 10;

n is selected from 1,2 and 3;

r is selected from 0,1 and 2; and is

p is selected from 1,2,3 and 4.

2. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, wherein L ₁ And L ₂ Is absent.

3. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 or2, wherein W ₁ And W ₂ Are all-O-.

4. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, which is a compound represented by the general formula (II):

wherein:

R ^2b is selected from- (CR) ^u R ^v ) _s -5 to 10 membered heteroarylWherein said 5-to 10-membered heteroaryl is optionally substituted by a group selected from halogen, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl, C _1-6 Haloalkyl and C _1-6 Substituted with one or more substituents of haloalkoxy; r ^u And R ^v Are the same or different and are each independently selected from the group consisting of hydrogen, halogen, hydroxy, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl radical, C _1-6 Haloalkyl and C _1-6 A haloalkoxy group;

s is selected from 0,1 and 2;

ring A, L, R ¹ And p is as defined in claim 1.

5. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4, wherein R ^2a And R ^2c Are all hydrogen atoms.

6. A compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 4 or 5, wherein R ^2b is-CH ₂ -5 to 6 membered heteroaryl, wherein said 5 to 6 membered heteroaryl is optionally selected from halogen, hydroxy, cyano, nitro, C _1-6 Alkyl radical, C _1-6 Alkoxy radical, C _1-6 Hydroxyalkyl radical, C _1-6 Haloalkyl and C _1-6 Haloalkoxy is substituted with one or more substituents.

7. The compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6, wherein ring a is a 6-to 10-membered aryl group, preferably phenyl.

8. The compound represented by the general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 7, which is a compound represented by the general formula (III):

wherein:

t is 1 or 2;

L、R ¹ and p is as defined in claim 1.

9. The compound of formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8, wherein L is- (CH) ₂ ) _m -, any one of them-CH ₂ -is optionally replaced by-O-, and m is selected from 1,2,3, 4, 5 and 6.

10. The compound of formula (I) according to any one of claims 1 to 9, wherein R is ¹ Are the same or different and are each independently selected from the group consisting of hydrogen, halogen and C _1-6 An alkoxy group; preferably, R ¹ Is C _1-6 An alkoxy group; more preferably, R ¹ Is methoxy.

11. A compound of general formula (I) or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 10, wherein p is 1.

12. A compound of general formula (I) according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, selected from the following compounds:

13. a compound represented by the general formula (IA):

wherein:

m is an amino protecting group, preferably allyl;

ring A, L ₁ 、L ₂ 、L、W ₁ 、W ₂ 、Z ¹ 、Z ² 、Z ³ 、R ¹ And p is as defined in claim 1.

14. A compound of formula (IA) or a salt thereof according to claim 13, selected from the following compounds:

15. a process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1, which process comprises:

removing amino protecting group from the compound shown in the general formula (IA) or salt thereof to obtain the compound shown in the general formula (I) or pharmaceutically acceptable salt thereof,

wherein:

m is an amino protecting group, preferably allyl;

16. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 12, together with one or more pharmaceutically acceptable carriers, diluents or excipients.

17. Use of a compound of general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 in the manufacture of a medicament for the inhibition of KAT; wherein said KAT is preferably KAT6, more preferably KAT6A and/or KAT6B.

18. Use of a compound of general formula (I) according to any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 16 for the preparation of a medicament for the treatment and/or prevention of cancer.

19. The use of claim 18, wherein the cancer is selected from the group consisting of lung cancer, mesothelioma, bone cancer, pancreatic cancer, skin cancer, head and neck cancer, brain cancer, melanoma, anal cancer, liver cancer, breast cancer, fallopian tube cancer, endometrial cancer, cervical cancer, ovarian cancer, vaginal cancer, vulvar cancer, hodgkin's disease, esophageal cancer, colorectal cancer, small bowel cancer, stomach cancer, thyroid cancer, parathyroid cancer, adrenal cancer, soft tissue sarcoma, penile cancer, testicular cancer, prostate cancer, leukemia, B-cell lymphoma, bladder cancer, urethral cancer, ureteral cancer, renal cell carcinoma, renal pelvis cancer, central nervous system tumor (CNS), primary CNS lymphoma, spinal cord tumor, glioma, brain glioma, pituitary adenoma, and squamous cell carcinoma; preferably breast cancer, prostate cancer, lung cancer, pancreatic cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, brain glioma, B cell lymphoma, liver cancer and leukemia; wherein the breast cancer is preferably ER ⁺ Breast cancer or ER ⁺ /HER2 ^- Breast cancer; wherein the lung cancer is preferably non-small cell lung cancer; wherein the prostate cancer is preferably castration-resistant prostate cancer.